COVID-19 treatment: therapeutic targets and mechanisms of action
COVID-19 involves the interplay of 500+ viral and host proteins and factors,
providing many therapeutic targets. In addition to direct antiviral activity, many
treatments may be beneficial by supporting immune system function or by minimizing
secondary complications. Here is a partial list of mechanisms of action and therapeutic
targets for COVID-19 treatments.
Mechanisms that prevent SARS-CoV-2 from entering host cells.
Entry inhibition mechanisms targeting viral proteins.
1. Spike/ACE2 blockade via RBD-targeting antibodies
Monoclonal antibodies or recombinant decoys that specifically bind the receptor-binding domain (RBD) of the spike protein, preventing attachment to ACE2 receptors on host cells1-4.
Possible treatments: bamlanivimab, casirivimab/imdevimab, tixagevimab/cilgavimab, regdanvimab, etesevimab, APN01, STI-4398, griffithsin, cyanovirin-N, RBD-binding antiviral peptides, BA7535, 17T2, 87G7, 10-5B, AZD3152, S2K146, GAR05, ZCP3B4, P2-1B1, P4J15, KXD03, VIR-7229, BD55-1205, P5-1C8, P5S-2A9, D1F6, A19-46.1, COV2-2196, S309, SP1-77, SW186, LY-CoV1404, BA7208, S2X324, P2S-2E9, 6-2C, 1G11, CR3022, ADG20, Ab246, DH1047, AB2-122, S2H97, XMA09, C68, GAR12, ION_300, Nanosota-9, Ma16B06, 1p1B10, Tnb04-1, Nb1, Nb2, W25, Nb4, 3-2A2-4, C5G2, RBD-409, RBD-951, 2130-1-0114-112
2. S2-targeting monoclonal antibodies (fusion domain inhibitors)
Monoclonal antibodies binding conserved epitopes within the spike protein's S2 domain, inhibiting viral fusion and preventing the virus from entering host cells after initial ACE2 binding4.
Possible treatments: Mab3-2, S2-4D, S2-5D, S2-8D, S2E7, 3D1, RAY53, hMab5.17, S2A9, R3DC23, 79C11
3. Spike glycoprotein cleavage inhibition
Targeting the proteolytic cleavage sites (S1/S2 and S2') of the spike protein to prevent the conformational changes required for membrane fusion2,5,6 .
Possible treatments: camostat mesylate, nafamostat, aprotinin
4. NTD (N-terminal domain) targeting antibodies
Monoclonal antibodies that bind to the N-terminal domain of the spike protein, which can disrupt viral attachment and entry4,7.
Possible treatments: 4A8, 4-8, DH1050, S2X333, 5-7, C1717, C1520, C1791, K501SP6, C1596, N235
5. Spike protein conformational stabilizers
Compounds that lock the spike protein in its pre-fusion conformation, preventing the structural changes required for membrane fusion2,7,8 .
Possible treatments: designed peptides mimicking stabilizing mutations, fingolimod, toremifene, cholecalciferol, calcifediol, famprofazone, flupentixol, oxyphenonium, trazodone, linoleic acid
6. Spike protein glycan shield disruptors
Targeting the extensive glycan shield on the spike protein that protects key epitopes from immune recognition and may play a role in host cell binding.
Possible treatments: glycosidase inhibitors, lectins, mannose-binding compounds
7. Fusion peptide inhibitors
Possible treatments: EK1, IPB02, EK1C4, HR2P, 76E1, C20.119, COV44-62, COV44-79, VN01H1, VP12E7, C77G12, fp.006, fp.007
8. Small molecule membrane fusion inhibitors
Small molecules that inhibit the fusion of the SARS-CoV-2 viral envelope with host cell membranes by directly targeting viral spike protein interactions or altering membrane properties critical for fusion7,9,10 .
Possible treatments: umifenovir, arbidol, nelfinavir, glycyrrhizin, ZINC000014930714, soyasaponin I (oleanane-type triterpenoid HR1 binders)
9. Phenothiazines
Compounds that have shown potential in inhibiting SARS-CoV-2 entry by binding to the spike protein, preventing its proteolytic cleavage necessary for viral entry5,11.
Possible treatments: chlorpromazine, thioridazine, haloperidol
10. Spike protein disorder-to-order transition targeting
Stabilization of disordered states in the spike protein, particularly in the S2 subunit, preventing the conformational changes required for membrane fusion and viral entry12.
Possible treatments: disorder stabilizers, conformation-selective binders, fusion-incompetent state stabilizers
11. RBD pocket-2 allosteric binders (α1/α2 cleft near Asn343)
Small molecules that bind the hydrophobic cleft between RBD helices α1-α2 (site 2). Binding (Phe338/Phe342/Phe374/Trp436) can be partially occluded by the Asn343 glycan but nevertheless allosterically perturbs RBD dynamics, reduces ACE2 interaction, and disfavors the open state8.
Possible treatments: fingolimod, calcifediol, cholecalciferol, salmeterol, betaxolol, hesperetin, catechin
12. RBD free-fatty-acid (FFA) pocket stabilizers (site 4)
Ligands of the linoleic-acid pocket (Tyr365/Tyr369/Phe374/Phe377/Tyr380) that stabilize the closed Spike trimer and indirectly reduce ACE2 binding; behaves as an allosteric “lock” on the RBD8.
Possible treatments: toremifene, cholecalciferol, famprofazone, flupentixol, oxyphenonium, trazodone, linoleic acid
13. Spike S-palmitoylation (ZDHHC5) dependence
ZDHHC5-mediated palmitoylation of the S cytosolic tail is needed for S-mediated fusion and efficient virion production; lowering palmitate supply or palmitoylation blocks infectivity13.
Possible treatments: 2-bromopalmitate, TVB-2640 (FASN inhibitor)
14. Spike NTD conserved triad (Q134-F135-N137)
A strictly conserved triad of amino acids (Q134-F135-N137) in the Spike N-terminal domain (NTD) acts as a "conformational transducer." Upon binding to host gangliosides, this triad initiates an allosteric "conformational wave" that propagates through the NTD to unmask the RBD on the neighboring protomer7.
Possible treatments: peptidomimetics, macrocycles, triad-competitive binders
15. Trivalent/multivalent miniprotein inhibitors
Computationally designed homotrimeric proteins (minibinders) that simultaneously engage all three receptor-binding domains (RBDs) of the SARS-CoV-2 spike trimer. This trivalent binding mode generates picomolar avidity, locking the trimer to prevent ACE2 interaction, and may confer resilience against viral escape mutations that defeat monomeric binders or monoclonal antibodies14.
Possible treatments: TRI2-2, AHB2 (monomer precursor)
16. S2 Stem-helix conformational locking
Antibodies targeting the hydrophobic stem-helix region prevent the S2 subunit from refolding and pulling viral/host membranes together, effectively freezing the virus in a pre-fusion intermediate2,4.
Possible treatments: CV3-25, CC25.106, CC99.103, S2P6, 7B2, WS6, S2-4A, hr2.016, CC68.109, 28D9, 1.6C7, B6, IgG22, H17, H145
17. Multivalent Spike cross-linking (AMETA)
Engineered IgM scaffolds or multivalent nanobodies (AMETA) that cross-link Spike trimers (in cis on the same virion or in trans between virions) to aggregate viral particles and prevent membrane fusion2,4.
Possible treatments: AMETA (adaptive multi-epitope targeting with enhanced avidity), IgM-scaffolded nanobodies, MN235, IgM-14, MR14, Nb4-16t, 79C11-Trimer, Nb6 Tribody, mi3-1C4, XMA04-mi3, LS-B-B2
18. Spike premature triggering (postfusion inactivation)
Antibodies or compounds that induce premature shedding of S1 and triggering of Spike into the postfusion state in the absence of target membranes, effectively inactivating the virus before it can engage host cells2.
Possible treatments: CV3-1, receptor-mimetic antibodies
19. Spike-CD147 interface blockade
Targeting the hydrogen-bonding interface between CD147 and the Spike RBD "up" conformation to prevent ACE2-independent entry15.
Possible treatments: meplazumab, competitive RBD binders
20. Targeting conserved structural Asn/Cys residues
Targeting conserved N-glycosylated asparagine and disulfide-bonding cysteine residues on the Spike protein to destabilize its architecture, lock the RBD in a "down" conformation, and prevent viral entry16.
Possible treatments: L-asparaginase, phytic acid, amygdalin, apigenin, kaempferol, candesartan, enalapril, quinapril, remdesivir
21. Viral envelope phosphatidylserine (PtdSer) masking
Enveloped viruses including SARS-CoV-2 and HIV expose phosphatidylserine (PtdSer) on their outer envelope leaflet, mimicking apoptotic cells to enhance interactions with host cell receptors (TIM-1, TIM-4) and facilitate viral entry. Masking or neutralizing PtdSer on the viral surface can block this apoptotic mimicry mechanism17.
Possible treatments: annexin V, bavituximab, PtdSer-targeting antibodies, diannexin
22. SCORE-A lateral RBD epitope targeting antibodies
Broadly neutralizing antibodies that bind the super-conserved SCORE-A lateral epitope on the RBD. They rigidify the lateral α2-helix and β4-β5 hairpin, providing stable anchoring while leaving the receptor-binding motif (RBM) partially mobile3.
Possible treatments: XGI-183, S309 (sotrovimab), VIR-7832, SA58
23. SCORE-B RBM apex-clamping antibodies
Antibodies targeting the super-conserved SCORE-B epitope near the tip of the RBD. They rigidly clamp the RBM apex, directly and sterically blocking ACE2 receptor engagement while tolerating mutations in peripheral flexible loops3.
Possible treatments: XGI-198, XGI-203, SA55
24. SCORE-C cryptic inner face allosteric antibodies
Antibodies targeting the highly conserved SCORE-C cryptic epitope on the inner face of the RBD. Rather than directly competing for the ACE2 binding site, they allosterically loosen and destabilize the RBM loop, indirectly impairing receptor engagement3.
Possible treatments: XGI-171, CR3022, EY6A
25. SD1 (Subdomain 1) targeting antibodies
Antibodies targeting the subdomain 1 (SD1) of the spike protein. These antibodies typically do not block ACE2 binding directly but induce conformational changes that destabilize the S protein or lock the RBD in transitional states4.
Possible treatments: S3H3, P008_60, sd1.040, C68.59, MO11
Targeting Host Proteins/Factors
Entry inhibition mechanisms targeting host proteins/factors.
26. TMPRSS2 inhibition
Possible treatments: camostat, nafamostat, bromhexine, gabexate mesylate, N-0385, Scutellaria barbata, linolenic acid, aprotinin
27. ACE2 modulation
Modulate ACE2 receptor expression, shedding, or availability to reduce viral docking1,5,9,20,21,26-28 .
Possible treatments: lisinopril, losartan, valsartan, candesartan, enalapril, telmisartan, resveratrol, berberine, estradiol, melatonin, artefenomel, quercetin, fosinopril, aliskiren, recombinant IL-13
28. Soluble ACE2 decoys
Engineered soluble forms of human ACE2 that act as decoys, competitively binding to the SARS-CoV-2 spike protein. This prevents viral particles from interacting with membrane-bound ACE2 on host cells, effectively blocking viral entry26,29.
Possible treatments: recombinant human ACE2 (rhACE2), ACE2-Fc fusion proteins, ACE2(M)-Fc
29. Heparan sulfate mimicry
Compete with heparan sulfate proteoglycans (HSPGs) to disrupt initial viral attachment7,13,20,30,31 .
Possible treatments: heparin, heparan sulfate mimetics, carrageenan, fucoidan, pentosan polysulfate, necuparanib, PG545
30. Cathepsin B/L inhibition
Inhibit endosomal proteases Cathepsin B and L, which cleave the spike protein to facilitate viral entry in cells lacking TMPRSS2 (e.g., neurons). Cathepsin B is specifically identified as the critical protease for neuronal entry1,5,6,10,13,20-24,26,32,33 .
Possible treatments: CA-074-ME, SB412515, teicoplanin, MDL-28170, E-64d (aloxistatin), hydroxychloroquine, chloroquine, clofazimine, rifampicin, saquinavir, astaxanthin, dexamethasone, clenbuterol, linolenic acid
31. Integrin targeting
Block integrin receptors - especially α2β1 (ITGA2) and α5β1, αvβ3 - involved in ACE2-independent entry20,21,34-36 .
Possible treatments: cilengitide, SB273005, RGD peptide inhibitors, anti-ITGA2 antibodies, obtustatin, dioscin, natalizumab
32. Neuropilin-1 targeting (blockade & expression suppression)
Blocking or down-regulating cell-surface Neuropilin-1 (NRP1) cuts off an auxiliary SARS-CoV-2 entry route and dampens downstream IL-6-mediated neuroinflammation13,20,21,36-38 .
Possible treatments: EG00229, soluble VEGF-A165b, VEGF-A inhibitors, meclizine, siRNA-NRP1
33. Lipid raft disruption
Possible treatments: simvastatin, fluvastatin, methyl-β-cyclodextrin, 25-hydroxycholesterol, nystatin, filipin
34. Surfactant inactivation
Disrupt viral envelopes or spike-receptor interactions via surfactant activity40.
Possible treatments: poloxamers, chlorhexidine
35. Inhibition of clathrin-mediated endocytosis or endosomal acidification
Inhibit clathrin-mediated endocytosis or endosomal acidification to prevent viral internalization5,10,21,22,25 .
Possible treatments: chloroquine, hydroxychloroquine, dynasore, mitmab, bafilomycin A1, umifenovir, Pitstop2, Dyngo4a, OcTMAB
36. Furin inhibition
Possible treatments: decanoyl-RVKR-chloromethylketone, MI-1851, naphthofluorescein
37. HER2 (ErbB2) signaling inhibition
Blocking host receptor-tyrosine-kinase HER2 prevents spike-triggered signaling and clathrin-mediated uptake, reducing early SARS-CoV-2 entry and downstream replication41,42.
Possible treatments: lapatinib, AG879, CP-724714
38. AXL receptor blockade
AXL tyrosine-kinase binds the spike N-terminal domain and mediates ACE2-independent entry; knockout or pharmacologic inhibition sharply reduces SARS-CoV-2 infection in pulmonary and bronchial cells13,20,21,35,43 .
Possible treatments: bemcentinib (BGB-324), gilteritinib, cabozantinib, soluble AXL protein, recombinant NTD protein
39. CD147 (Basigin) antagonism
Monoclonal antibodies block CD147, an inducible receptor upregulated by SARS-CoV-2 via AHR activation. CD147 binds the Spike RBD to facilitate ACE2-independent entry, particularly in ACE2-deficient cells. Blockade prevents viral entry and restores immune homeostasis10,13,15,20,21,35,36,38,43 .
Possible treatments: meplazumab, anti-CD147 peptide decoys
40. KREMEN1 & ASGR1 inhibition
Receptome profiling identifies KREMEN1 (Wnt co-receptor) and ASGR1 (asialoglycoprotein receptor) as functional alternate receptors that enable ACE2-independent entry; antibodies, soluble ectodomains or siRNA can block this route13,20,21,35,43 .
Possible treatments: anti-KREMEN1 mAb, anti-ASGR1 mAb, ASGR1-Fc decoys, siRNA-KREMEN1/ASGR1, cocktail antibodies targeting ASK receptors
41. DC-SIGN / L-SIGN (CLR) blockade & soluble lectins
C-type lectin receptors DC-SIGN and L-SIGN capture spike glycans to promote attachment; anti-CLR antibodies, glycodendrimers or soluble lectins (griffithsin, cyanovirin-N) competitively block this step13,20,43,44 .
Possible treatments: polyman-26, glycodendrimers, anti-DC-SIGN mAb, griffithsin, cyanovirin-N, mannan, fucoidans, lectin inhibitors
42. SR-B1 (SCARB1) blockade
HDL-scavenger receptor B type 1 binds spike-HDL complexes and facilitates ACE2-dependent entry; small-molecule SR-B1 antagonists or neutralizing antibodies reduce infection13,20,45 .
Possible treatments: BLT-1, ITX5061, anti-SR-B1 mAb
43. KIM-1 / TIM receptor family antagonism
Targeting members of the T-cell immunoglobulin and mucin domain (TIM) family. In the kidney, Kidney Injury Molecule-1 (KIM-1/TIM-1) acts as an attachment factor for SARS-CoV-2. TIM-1 and TIM-4 can enhance viral infection by binding to phosphatidylserine (PS) on the viral envelope, promoting ACE2-dependent endocytosis20,46.
Possible treatments: anti-KIM-1 mAb, KIM-1-competitive peptides, siRNA-KIM1
44. PIKfyve & PIP5K1C inhibition
Endosomal lipid-kinase PIKfyve generates PI(3,5)P₂ required for late-endosome fusion; inhibitors (apilimod, UNI418) block cathepsin-dependent entry across variants13,33,47,48 .
Possible treatments: apilimod, UNI418, YM-201636, WX8-125
45. Epigenetic suppression of cathepsin-L maturation
EHMT2 inhibitors diminish lysosomal maturation of cathepsin-L, preventing spike S2' cleavage and endosomal fusion, thereby blocking SARS-CoV-2 entry across ancestral and variant strains49.
Possible treatments: UNC0642, UNC0638, BIX01294
46. MET (c-Met/HGFR) receptor inhibition
Blocking MET tyrosine-kinase disrupts coronavirus internalization and early replication steps, capmatinib shows broad anti-CoV activity in vitro42.
Possible treatments: capmatinib, tepotinib, crizotinib
47. Nrf2-mediated suppression of ACE2 and TMPRSS2
Activation of Nrf2 (e.g., by PB125 or DMF) downregulates ACE2 and TMPRSS2 mRNA, reducing viral docking and spike priming in host cells50,51.
Possible treatments: PB125, dimethyl fumarate, sulforaphane
48. Calcium-activated TMEM16 scramblase inhibition
Blockade of Ca2+-activated TMEM16F lipid-scramblase/ion-channel suppresses spike-driven membrane fusion and triggers antiviral autophagy, yielding multi-log viral reduction in cell and animal models5,13,19,21 .
Possible treatments: niclosamide, clofazimine, fluoxetine
49. Transferrin receptor (TfR) blockade
TfR serves as an ACE2-independent entry receptor that can transport SARS-CoV-2 from cell membrane to cytoplasm. Anti-TfR antibodies or competitive peptides can prevent viral entry and reduce pathological lung injury13,20,35,52 .
Possible treatments: anti-TfR antibodies, TfR-competitive peptides, transferrin-derived blocking agents
50. DPP4 (dipeptidyl peptidase-4) inhibition
DPP4 serves as a cell surface binding target for the spike protein RBD and can enhance SARS-CoV-2 infection by promoting ACE2 receptor-dependent endocytosis. DPP4 inhibitors may provide dual benefits for COVID-19 patients with diabetes and reduce cytokine storm20,53.
Possible treatments: sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin
51. Myosin heavy chain 9 (MYH9) inhibition
MYH9 acts as a coreceptor that enhances SARS-CoV-2 infection by promoting endocytosis dependent on ACE2, particularly in cells with low ACE2 expression. Inhibition can significantly reduce viral infection20.
Possible treatments: myosin inhibitors, blebbistatin, 2, 3-butanedione monoxime
52. GRP78 (glucose regulated protein 78) targeting
Cell surface GRP78 serves as an attachment factor that promotes viral endocytosis by interacting with spike protein and endogenous ACE2. GRP78 also acts as a viral protein chaperone. Small molecule inhibitors show antiviral efficacy20,35,54 .
Possible treatments: HA15, kifunensine, GRP78 antagonists, hMAb159, YUM70
53. TTYH2 (tweety family member 2) inhibition
TTYH2 binds to the RBD domain of spike protein similar to ACE2 and contributes to myeloid cell inflammatory responses. Blocking TTYH2 may reduce excessive inflammatory reactions20.
Possible treatments: TTYH2 antagonists, chloride channel blockers
54. TIM/TAM family receptor enhancement
TIM-1 and TIM-4 phosphatidylserine receptors directly interact with PS on SARS-CoV-2 outer leaflet, enhancing viral infection by promoting ACE2-dependent endocytosis. These represent druggable targets for intervention20.
Possible treatments: PS receptor antagonists, TIM-1/TIM-4 blocking antibodies
55. ADAM17 protease inhibition
ADAM17 is triggered by spike protein to cleave ACE2, leading to extracellular ACE2 detachment and enhanced host protease activity that promotes viral cytoplasmic fusion1,20.
Possible treatments: ADAM17 inhibitors, metalloprotease inhibitors, TAPI-0, TAPI-1
56. Ezrin activation
The Ezrin protein can inhibit viral infection by reducing the expression of key entry receptors like ACE2 and TLRs. Peptides derived from Ezrin have shown potential in inhibiting viral pneumonia20.
Possible treatments: Ezrin peptides
57. LY6E activation
The host cell surface receptor LY6E inhibits SARS-CoV-2 infection by interfering with spike protein-mediated membrane fusion and the necessary cytoskeletal rearrangement. Augmenting LY6E function could serve as a defensive therapeutic approach20.
Possible treatments: LY6E agonists
58. IFITM3 activation
The host protein IFITM3 is an interferon-induced restriction factor that prevents SARS-CoV-2 invasion by regulating host cell membrane fluidity to block the fusion of the viral envelope with the plasma membrane. Enhancing IFITM3 activity is a potential host-directed antiviral strategy20.
Possible treatments: IFITM3 activators
59. CD209 and CLEC4L targeting
C-type lectin receptors that facilitate viral attachment through interaction with spike glycans. Blocking these receptors can reduce viral entry particularly in dendritic cells and macrophages10.
Possible treatments: anti-CD209 antibodies, mannose analogs, glycodendrimers
60. AAK1 (AP2-associated protein kinase-1) inhibition
Blocking AAK1-dependent clathrin-mediated endocytosis can reduce viral internalization; baricitinib is a dual JAK/AAK1 inhibitor proposed to impede SARS-CoV-2 entry10,22.
Possible treatments: baricitinib
61. TMEM106B-dependent lysosomal entry
Endo-lysosomal membrane protein TMEM106B regulates lysosome function and cooperates with V-ATPase; required for SARS-CoV-2 infection (facilitates cathepsin/LAMP1+ compartment entry)13,35,47 .
Possible treatments: TMEM106B modulators (experimental)
62. V-ATPase-driven vesicle acidification
ATP6AP1/ATP6V1A subunits acidify endosomes/lysosomes enabling cathepsin-dependent S2' activation and late entry; nsp6 and M interact with these subunits13,31,44,47,55 .
Possible treatments: etidronate, alendronate
63. Rab7-Mon1/CCZ1-HOPS late endosome maturation
RAB7A with its GEF (Mon1-Ccz1: CCZ1/CCZ1B/C18orf8) and HOPS (VPS39) traffic incoming virions to fusion sites and influence ACE2 surface levels13.
Possible treatments: Rab7 inhibitors (CID-1067700), vacuolin-1
64. Retromer/retriever/CCC-mediated ACE2 recycling
VPS29/VPS35/VPS35L, SNX27 and CCC (CCDC22/CCDC93/COMMDs) drive retrograde recycling; knockout lowers ACE2 surface and blocks entry13,47,56 .
Possible treatments: retromer stabilizer R55, WASH/Arp2/3 inhibitors (CK-666)
65. Arp2/3-WASH actin branching for endosomal scission
ACTR2/ACTR3/ARPC3/ARPC4 and WASHC4 support retromer budding and receptor recycling required for efficient entry13.
Possible treatments: CK-666, CK-869
66. AP-1 adaptor complex-dependent trafficking
AP1B1/AP1G1 support early (TMPRSS2-biased) entry in airway cells by positioning proviral cargos and routes13,31.
Possible treatments: brefeldin A, AP-1 inhibitors
67. AHR-mediated receptor modulation (CD147 induction / ACE2 regulation)
Activated Aryl Hydrocarbon Receptor (AHR) translocates to the nucleus to drive the transcription of CD147 (Basigin), promoting an inducible, ACE2-independent viral entry route. AHR antagonists can prevent this receptor upregulation and limit extended infection15,57,58 .
Possible treatments: CH-223191, GNF351, pelargonidin-class AHR modulators, StemRegenin 1 (AHR antagonist 5)
68. Heparan-sulfate (HS) clusters as primary attachment receptor
Direct nanoscopy shows SARS-CoV-2 binds tall HS nanoclusters that mediate cell-surface attachment and subsequent endocytic uptake; ACE2 is engaged downstream post-endocytosis30.
Possible treatments: pixantrone, heparinase I/II/III, heparin/HS mimetics (e.g., fucoidan, pentosan polysulfate, PG545, necuparanib)
69. Macropinocytosis/dynamin-dependent endocytosis blockade
Internalized virions reside in vesicles that can contain multiple particles; dynamin inhibition or dominant-negative DNM2 reduces uptake and gene expression; pattern and vesicle size are consistent with macropinocytosis as a major entry route5,21,30,34 .
Possible treatments: EIPA (amiloride derivative), dynasore, DNM2-K44A, amiloride, DYN101
70. Phosphatidylinositol 4-kinase III beta (PI4KIIIβ) inhibition
PI4KIIIβ is a host kinase involved in viral entry and replication. It generates phosphatidylinositol 4-phosphate (PI4P), which is essential for regulating lipid membrane composition and trafficking events hijacked by coronaviruses for entry and the formation of replication organelles48.
Possible treatments: PIK-93, enviroxime, bithiazole derivatives, CUR-N399
71. Histamine H1 receptor (HRH1) antagonism
Blockade of the histamine H1 receptor, a potential alternative receptor for SARS-CoV-2 entry. Antihistamines may also offer immunomodulatory benefits5,26.
Possible treatments: acrivastine, azelastine, bilastine, desloratadine, diphenhydramine, fexofenadine, loratadine, promethazine, rupatadine, triprolidine
72. Bile acid receptor modulation (FXR/TGR5)
Activation of bile acid receptors like FXR and TGR5, which can downregulate ACE2 expression and exert anti-inflammatory effects, thereby reducing both viral entry and immunopathology5.
Possible treatments: chenodeoxycholic acid, ursodeoxycholic acid
73. Variant-specific transmembrane serine protease (TTSP) inhibition (Hepsin, KLK13, etc.)
SARS-CoV-2 variants evolved to use a diverse range of host transmembrane serine proteases (TTSPs) beyond TMPRSS2 for spike protein activation. For example, Alpha and Delta show enhanced binding to Hepsin, while Beta can utilize Kallikrein 13 (KLK13)6,21.
Possible treatments: camostat, broad-spectrum TTSP inhibitors
74. Extracellular vimentin (eVIM) attachment factor blockade
Extracellular vimentin (eVIM) acts as a host attachment factor or co-receptor for SARS-CoV-2, bridging the virus to its primary receptor on the host cell surface. Blocking eVIM with monoclonal antibodies prevents this interaction, thereby inhibiting viral entry59.
Possible treatments: hzVSF-v13, anti-eVIM monoclonal antibodies
75. ITGB3 (Integrin beta 3) blockade
Blocking ITGB3, an integrin receptor involved in platelet aggregation and immune cell signaling. ITGB3 plays a role in coagulation abnormalities and immune dysregulation in COVID-19. Inhibition of ITGB3 could mitigate microthrombosis and inflammatory responses34.
Possible treatments: Xemilofiban, integrin inhibitors
76. Bmal1 inhibition / REV-ERB agonism
Modulating the host circadian clock pathway to reduce ACE2 expression and limit cell-cell fusion. This can be achieved by inhibiting the transcription activator Bmal1 or by using REV-ERB agonists, which repress Bmal1 and downregulate ACE221.
Possible treatments: REV-ERB agonists, Bmal1 inhibitors
77. TULP3-mediated ciliary trafficking inhibition
Tubby Like Protein-3 (TULP3) acts as a pivotal adaptor protein that governs the trafficking of ACE2 to the primary cilium axoneme, partially through interaction with the IFT-A complex. TULP3 depletion significantly reduces ciliary ACE2 enrichment and impairs the entry of SARS-CoV-2 variants60.
Possible treatments: TULP3-ACE2 interface inhibitors, ciliary trafficking blockers, TULP3-IFT-A interaction disruptors, tubby-domain peptidomimetics
78. Primary cilium biogenesis disruption (IFT88 / ARL13B)
The presence of ACE2-enriched primary cilia is a determinant of host cell tropism and viral invasio. Genetic perturbation of key ciliogenesis genes, such as IFT88 or ARL13B, leads to deciliation or structural defects that significantly diminish SARS-CoV-2 infectivity in lung and retinal epithelial cells60.
Possible treatments: ciliogenesis inhibitors, intraflagellar transport modulators
79. CD169 (Siglec-1) mediated trans-infection
CD169 is a sialic-acid-binding I-type lectin on macrophages and dendritic cells that captures SARS-CoV-2 via the Spike NTD. While macrophage infection is often abortive (leading to RIG-I/MDA-5 inflammation), CD169 facilitates efficient trans-infection to ACE2-expressing cells35.
Possible treatments: anti-CD169 mAbs
80. CLEC4G (LSECtin) attachment factor blockade
CLEC4G is a C-type lectin expressed in liver and lymph nodes that binds SARS-CoV-2 Spike NTD and RBD. Soluble CLEC4G or knockdown significantly inhibits viral entry in ACE2-independent pathways35.
Possible treatments: soluble CLEC4G, anti-CLEC4G antibodies
81. LDLRAD3 N-terminal domain interaction inhibition
LDLRAD3 is a membrane-associated protein and E3 ubiquitin ligase regulator that binds the SARS-CoV-2 Spike NTD with high affinity, and mediates viral entry in neurons and myeloid cells lacking ACE2; soluble LDLRAD3 blocks this pathway35.
Possible treatments: soluble LDLRAD3, anti-LDLRAD3 antibodies
82. TMEM30A (CDC50A) flippase subunit targeting
TMEM30A, the beta-subunit of the P4-ATPase phospholipid flippase, binds the Spike NTD and facilitates ACE2-independent entry. Loss-of-function studies confirm its necessity for infection in specific ACE2-deficient cell types35.
Possible treatments: anti-TMEM30A antibodies
83. LFA-1 mediated T-cell entry blockade
Lymphocyte Function-Associated Antigen 1 (LFA-1) acts as an alternative receptor mediating SARS-CoV-2 infection in T cells (Jurkat lines and primary CD4+ T cells), contributing to T-cell death and lymphopenia35.
Possible treatments: LFA-1 antagonists
84. CD4 receptor blockade
SARS-CoV-2 Spike (RBD and full-length) binds the N-terminal domain of CD4 with high affinity, enabling infection of T-helper cells. Soluble CD4 or neutralizing anti-CD4 antibodies suppress this infection route, which is linked to IL-10 dysregulation35.
Possible treatments: soluble CD4, ibalizumab, anti-CD4 antibodies
85. Ganglioside-mediated viral attachment blockade
Lipid raft-associated gangliosides (e.g., GM1) serve as the primary attachment receptors for the Spike NTD, acting as "electrostatic attractors." This interaction is essential to trigger the conformational change that exposes the RBD for ACE2 binding7.
Possible treatments: hydroxychloroquine, chloroquine, ganglioside mimetics, sialic acid analogs, tetravalent sialo-glycoclusters, anti-GBD peptides, neuraminidase inhibitors
86. HDAC6-mediated uncoating and signaling
HDAC6 binds unanchored ubiquitin chains on viral capsids to facilitate physical uncoating through cytoskeletal shear forces. It also regulates innate immune responses22.
Possible treatments: HDAC6 inhibitors (targeting ZnF domain)
87. p38 MAPK pathway inhibition (viral entry)
Blocking p38 MAPK signaling disrupts virus-induced membrane invagination and endocytosis initiation. The activated p38 signal acts as a trigger for viral internalization, representing a broad-spectrum antiviral target22.
Possible treatments: SB203580, losmapimod, doramapimod, ralimetinib
88. EGFR (Epidermal Growth Factor Receptor) inhibition
SARS-CoV-2 spike protein activates EGFR to enhance downstream signaling (ERK1/2, AKT) and upregulate survivin; inhibition reduces infection and inflammation23.
Possible treatments: apigenin-7-glucoside, quercetin, pistagremic acid, linolenic acid
89. Endosomal Calcium modulation
SARS-CoV-2 S2 refolding and membrane fusion are calcium-dependent; depleting calcium or blocking calcium interaction promotes reversible conformational changes that inhibit fusion2.
Possible treatments: calcium chelators, calcium channel blockers
90. NAE1 (Neddylation) pathway inhibition
The Nedd8-activating enzyme 1 (NAE1) pathway is required to maintain cellular levels of the host protease TMPRSS2. Inhibition of neddylation triggers the loss of TMPRSS2, preventing spike protein priming, syncytia formation, and viral entry61.
Possible treatments: pevonedistat (MLN4924), TAS4464
91. MUC1 (Mucin 1) ferroptosis inhibition
Membrane-bound MUC1 is a hub gene that inhibits ferroptosis and sensitizes cells to Vitamin E alleviation of oxidative injury via the GSK3B pathway. It also provides steric hindrance to pathogen entry62.
Possible treatments: surfactant modulators
92. AHR-mediated CD147 transcriptional upregulation
SARS-CoV-2 infection activates the Aryl Hydrocarbon Receptor (AHR), which translocates to the nucleus and binds the CD147 promoter, driving the inducible overexpression of CD147. This creates a positive feedback loop for extended viral entry and inflammation15.
Possible treatments: StemRegenin 1 (AHR antagonist 5), AHR antagonists
93. IL-13 mediated ACE2 transcriptional suppression
The Type-2 cytokine IL-13 significantly downregulates ACE2 mRNA and surface protein expression in human airway epithelial cells. This transcriptional suppression reduces the availability of the viral receptor, thereby inhibiting Spike protein attachment and preventing viral entry27.
Possible treatments: recombinant IL-13
94. HSC70-mediated clathrin-dependent viral internalization
Host heat shock cognate protein 70 (HSC70) interacts with the intracellular domain of the viral M protein via its substrate-binding domain. This interaction is critical for orchestrating viral internalization and directing the virion into host cells through the clathrin-mediated endocytosis (CME) pathway31.
Possible treatments: HSC70 inhibitors
95. HDL composition modulation
Modulation of high-density lipoprotein (HDL) composition can potentially block viral attachment to ACE2 receptors17.
Possible treatments: niacin
96. Host cell glycocalyx preservation
Maintaining the host cell glycocalyx provides a steric hindrance that restricts the viral spike protein from accessing the ACE2 receptor on the plasma membrane. Cells with naturally reduced surface glycosylation show markedly higher susceptibility to viral entry25.
Possible treatments: sialidase inhibitors
Mechanisms that disrupt the replication or assembly of SARS-CoV-2 within host cells.
Replication inhibition mechanisms targeting viral proteins.
97. RNA-dependent RNA polymerase (RdRp) inhibition
Possible treatments: remdesivir, molnupiravir, azvudine, bemnifosbuvir, deuremidevir, favipiravir, ribavirin, galidesivir, rifampicin, zidovudine, tenofovir, dolutegravir, raltegravir
98. Non-nucleoside RdRp inhibition
Possible treatments: suramin, dasabuvir, PPI-383
99. Main (M) protease (3CLpro) inhibition
Blocking Mpro prevents viral polyprotein cleavage and can minimize Mpro-driven mitochondrial dysfunction1,5,10,18-20,26,47,65-68 .
Possible treatments: paxlovid, lopinavir/ritonavir, atilotrelvir, ensitrelvir, ibuzatrelvir, leritrelvir, lufotrelvir, pomotrelvir, xiannuoxin, GC376, rupintrivir, masitinib, narlaprevir, Scutellaria barbata, disulfiram, grazoprevir, ofloxacin, oseltamivir, zanamivir, cobicistat, darunavir, atazanavir, dolutegravir, raltegravir
100. Papain-like protease (PLpro) inhibition
Blocking PLpro activity, which processes viral polyproteins and disrupts host immune response1,5,18,69-71 .
Possible treatments: GRL-0617, thiopurine analogs, diiodohydroxyquinoline, Scutellaria barbata, disulfiram
101. Nsp13 helicase inhibition
Possible treatments: myricetin, scutellarein, SSYA10-001, bananin, ivermectin, avasimibe, candesartan cilexetil, pranlukast, ursolic acid
102. Methyltransferase inhibition
Inhibit viral RNA capping by targeting nsp10/nsp16 complex.
Possible treatments: sinefungin, SAM analogs
103. Envelope (E) protein ion channel inhibition
Targeting the viroporin activity of the small envelope protein that forms pentameric ion channels and is involved in viral assembly and pathogenesis1,5.
Possible treatments: amantadine, rimantadine, hexamethylene amiloride
104. Nucleocapsid (N) protein inhibition
Disrupt N protein's RNA binding and oligomerization, preventing genome packaging. N is heavily sialylated in patients and infected cells; NEU1-regulated desialylation enhances N-RNA affinity, so preserving N sialylation further reduces replication5,73-77 .
Possible treatments: ebselen, PJ34, hesperetin, riluzole, CT05, CT10
105. Nucleocapsid protein intrinsically disordered region (IDR) targeting
Compounds targeting the disordered N-terminal domain (1-68), central linker region (181-248), or C-terminal domain (370-419) to disrupt RNA binding, liquid-liquid phase separation, and viral genome packaging12,73.
Possible treatments: RNA-binding inhibitors, LLPS disruptors, phase separation modulators, condensate destabilizers
106. Virion assembly disruption
Possible treatments: nitazoxanide, temoporfin, JNJ-9676, CIM-834, verteporfin
107. Nonstructural protein 1 (Nsp1) inhibition
Targeting Nsp1, which suppresses host gene expression by blocking mRNA entry into ribosomes and causing host mRNA degradation47.
Possible treatments: Nsp1-ribosome interaction inhibitors, compounds preventing Nsp1 C-terminal domain activity
108. Nsp1 flexible linker (129-147) targeting
Small molecules that stabilize or destabilize specific conformations of the disordered linker region between Nsp1 N-terminal and C-terminal domains, modulating its interaction with the ribosome and limiting viral translation inhibition12.
Possible treatments: designed peptidomimetics, small molecules stabilizing disorder-to-order transitions
109. Nsp1 Cu(II) binding region (163-167) targeting
Compounds that mimic or disrupt Cu(II) binding to the disordered region containing key residues W161 and H165, altering Nsp1 structural dynamics and function12.
Possible treatments: metal chelators, Cu(II) mimetics, W161/H165-targeting compounds
110. Nsp2 function inhibition
Blocking the activity of Nsp2, which may play roles in host cell environment modulation and interacts with prohibitin proteins.
Possible treatments: prohibitin-targeting compounds, small molecules disrupting Nsp2-host protein interactions
111. Nsp3 (multifunctional domains) inhibition
Targeting the large multi-domain non-structural protein 3, particularly its macrodomain (Mac1) that suppresses host immune response by removing ADP-ribose modifications, and the ubiquitin-like domain 1 (Ubl1) that mediates important interactions with other viral proteins for replication complex formation22,79.
Possible treatments: F2124-0890, ADP-ribose analogs, macrodomain inhibitors, thiopurine analogs, GRL-0617 derivatives, VE-112, VE-157, disulfiram, PLP_CoV2_3k, ebselen, AVI-4206, AVI-4636, AVI-92
112. Nsp4 membrane reorganization inhibition
Disrupting Nsp4's critical role in double-membrane vesicle (DMV) formation and organization of viral replication complexes, which are essential for creating protected environments for viral RNA synthesis22.
Possible treatments: K22, AM580, memantine, enoxacin, cetylpyridinium chloride, hexachlorophene
113. Nsp5-Nsp8 interaction disruption
Preventing essential protein-protein interactions between components of the viral replication machinery, particularly the interaction between Mpro (Nsp5) and the primase Nsp8, which is critical for the function of the replication-transcription complex.
Possible treatments: peptide-based inhibitors targeting interaction interfaces, α-ketoamides, small molecule PPI inhibitors, cyclic peptides
114. NSP6 autophagy and organelle modulation inhibition
Counteracting Nsp6's ability to limit autophagosome expansion, which may help the virus evade autophagy-mediated viral clearance55.
Possible treatments: autophagy enhancers specifically targeting Nsp6 mechanisms, compounds restoring normal autophagosome formation
115. Nsp7-Nsp8 primase complex disruption
Targeting the Nsp7-Nsp8 complex that functions as a primase for RdRp, essential for initiating RNA synthesis47.
Possible treatments: small molecules disrupting Nsp7-Nsp8 protein-protein interactions, compounds preventing primase activity
116. Nsp9 RNA-binding inhibition
Targeting Nsp9, an essential RNA-binding protein required for viral RNA synthesis and replication that functions through both RNA and DNA binding capabilities and potential dimerization. Nsp9 also sequesters let-7b, suppressing TLR7-mediated immunity47,80.
Possible treatments: suramin derivatives, nucleic acid analogs, small molecules targeting the dimerization interface, DNA-binding inhibitors, quinoline derivatives
117. Nsp10 cofactor inhibition
Blocking Nsp10, which serves as an essential cofactor for both Nsp14 (ExoN/N7-MTase) and Nsp16 (2'-O-MTase), thereby disrupting viral RNA processing and immune evasion47,81.
Possible treatments: compounds targeting Nsp10-Nsp14/Nsp16 interfaces, Nsp10 zinc finger inhibitors
118. Nsp13 helicase/triphosphatase inhibition
Blocking the multiple enzymatic functions of Nsp13, which possesses RNA helicase, NTPase, and RNA 5'-triphosphatase activities essential for viral replication and mRNA capping47,82.
Possible treatments: myricetin, scutellarein, SSYA10-001, triazole derivatives, bismuth salts, vapreotide, 1, 2, 3-triazole derivatives, HE602
119. Nsp14 dual-function inhibition
Targeting the bifunctional nonstructural protein 14 (Nsp14), which contains both N7-methyltransferase (N7-MTase) activity crucial for viral mRNA cap formation and 3'-5' exoribonuclease (ExoN) activity that provides proofreading during RNA replication, reducing mutation rates and maintaining viral genetic fidelity1,46,47,81,83 .
Possible treatments: ribavirin, sinefungin, aurintricarboxylic acid, GRL-0617-like compounds, Y3, suramin, ZINC09432058, tanshinone derivatives, thymoquinone, gossypol, SAM analogs
120. Nsp15 endoribonuclease inhibition
Mechanisms that target the viral endoribonuclease Nsp15, which helps SARS-CoV-2 evade host immune detection47,71,84 .
Possible treatments: acrylamide-based covalent inhibitors
121. Nsp16 2'-O-methyltransferase inhibition
Nsp16 functions as a 2'-O-methyltransferase that methylates the 5' cap of viral RNA, preventing degradation by host cells. Inhibiting this activity can impair viral RNA stability and replication1,20,47,85 .
Possible treatments: sinefungin, SAM analogs, 2'-O-methyltransferase inhibitors
122. Spike protein RNA packaging signal inhibition
Targeting the RNA packaging signal in the spike protein gene that may facilitate incorporation of genomic RNA into virions.
Possible treatments: oligonucleotides, small molecules specifically binding to RNA packaging signals
123. ORF3a viroporin blockade
Inhibiting the ion channel activity of ORF3a, which forms viroporins, induces apoptosis, and activates the NLRP3 inflammasome, contributing to viral pathogenesis and release5,71,86 .
Possible treatments: emodin, 5-hydroxymethyl-2-furaldehyde, adamantane derivatives, hexamethylene amiloride, potassium channel blockers, calcium channel blockers, diltiazem, austocystin D, N-acetyl-D-glucosamine
124. ORF3a N-terminal IDR (1-41) targeting
Disruption of the disordered N-terminal region of ORF3a that controls protein localization and retention at the plasma membrane, essential for viral assembly and immune evasion12.
Possible treatments: small molecules disrupting membrane localization, peptidomimetics, subcellular targeting disruptors
125. ORF3a TRAF-binding motif (36-40) targeting
Inhibition of the disordered TRAF-binding region that activates NF-κB and NLRP3 inflammasome pathways, reducing hyperinflammation and cytokine storms12.
Possible treatments: TRAF interaction inhibitors, selective NF-κB modulators, NLRP3 pathway disruptors
126. ORF6 nuclear transport disruption inhibition
Counteracting ORF6's antagonism of interferon signaling and disruption of nuclear transport, which prevents antiviral gene expression through sequestration of import factors.
Possible treatments: nuclear transport enhancers, karyopherin activators, importin-targeting compounds, selinexor derivatives
127. ORF7a/7b immunomodulation inhibition
Blocking ORF7a and ORF7b activities that modulate host immune response and potentially participate in viral assembly through interactions with host proteins and other viral components.
Possible treatments: small molecule inhibitors targeting protein-protein interactions, BST-2/tetherin-enhancing compounds, cyclophilin inhibitors
128. ORF8 immune evasion inhibition
Countering ORF8's interference with MHC-I-dependent antigen presentation and downregulation of interferon responses, which help the virus evade immune detection26.
Possible treatments: proteasome activators, ER stress modulators, MHC-I stabilizing compounds, IRE1α-targeting drugs, ATF6 pathway modulators
129. ORF9b mitochondrial targeting inhibition
Preventing ORF9b from suppressing host innate immunity through targeting mitochondria and disrupting MAVS signalosome formation, which impairs interferon responses46.
Possible treatments: mitochondrial function enhancers, TOM70 interaction inhibitors, DRP1 activators, MAVS pathway stimulators, mitochondrial antiviral compounds
130. ORF10 function inhibition
Blocking the potential roles of ORF10 in viral pathogenesis and replication87.
Possible treatments: compounds disrupting ORF10-host protein interactions, CUL2 ubiquitin ligase complex inhibitors
131. Nsp10-Nsp14 ExoN interface PPI inhibition
Small molecules that occupy pockets at the nsp10-nsp14 interface to prevent nsp10-mediated activation of the ExoN proofreading enzyme. Blocking this PPI lowers proofreading and can sensitize SARS-CoV-2 to nucleoside analogs81,83.
Possible treatments: VT00180, VT00249, VT00123-R, VT00421, VT00218, bismuth(III) compounds
132. Nsp14 ExoN-hinge allosteric inhibition
Ligands that bind the hinge connecting ExoN and the N7-methyltransferase domain to perturb ExoN conformation/communication and reduce proofreading activity81.
Possible treatments: VT00079, VT00123-S, VT00218
133. Nsp14 ExoN His268 rotamer-state stabilization
Allosteric or proximal binders that bias the catalytic general base His268 toward the inactive orientation observed crystallographically, suppressing DEDDh ExoN activity and enhancing NA efficacy81.
Possible treatments: His268-rotamer stabilizers, metal-site-adjacent allosteric binders
134. Nsp10 allosteric ligands / targeted degradation
Ligands for two non-interface allosteric pockets on nsp10 (sites III & IV) that could lead to allosteric inhibitors of nsp10 function or serve as handles for nsp10-directed PROTACs to disable ExoN/MTase cofactor activity81.
Possible treatments: VT00258, VT00259, nsp10-directed PROTAC warheads
135. Membrane (M) protein assembly inhibition
Small molecules that bind the conserved coronavirus membrane (M) protein and trap it in non-productive conformations (e.g., stabilize the TM-domain dimer or the Mshort state), preventing Mlong conversion, multimerization, membrane curvature, and virion assembly. Resistance clusters at pocket residues (e.g., Y95, S99, N117, P132), yet conservation across sarbecoviruses suggests broad coverage31,47,78 .
Possible treatments: JNJ-9676, CIM-834
136. Mpro targeted degradation (host E3 ligase recruitment)
Host E3 ligases FBXO22, ZBTB25 and Parkin can ubiquitinate Mpro/3CLpro and drive its proteasomal degradation; pharmacologic recruitment may lower viral fitness and complement catalytic-site inhibitors66-68.
Possible treatments: Mpro-PROTACs recruiting FBXO22/ZBTB25/Parkin, VHL/CRBN-based degraders
137. Mpro (3CLpro) proteolysis by host MMP14 or PLpro-activated MMP14
Membrane-type matrix metalloproteinase-14 (MMP14) selectively binds and cleaves SARS-CoV-2 3CLpro at loop-2 (G170|V171), eliminating protease activity and suppressing viral replication. An engineered zymogen (pro-PL-MMP14) carries a viral PLpro cleavage motif (LxGG) between the pro- and catalytic domains, enabling activation specifically in infected cells67.
Possible treatments: cat-MMP14 (soluble catalytic domain), pro-PL-MMP14 (PLpro-activated MMP14 proenzyme)
138. RdRp catalytic-site non-nucleoside inhibitors (NTP-entry blockers)
Small molecules that occupy the nsp12 catalytic pocket/NTP entry channel and modulate RNA/NTP binding, yielding mixed or competitive inhibition and blocking replication in cells64.
Possible treatments: rose bengal, 3-O-acetyl-11-keto-β-boswellic acid (AKBA), theaflavin-3-gallate, dryocrassin ABBA, meclinertant, omaveloxolone
139. RdRp Palm-site allosteric inhibitors (nsp12 Palm subdomain)
Ligands that bind an allosteric pocket in the Palm subdomain adjacent to the NTP entry channel, inducing noncompetitive inhibition and slowing polymerase catalysis64.
Possible treatments: venetoclax, omaveloxolone, meclinertant, dryocrassin ABBA, BMS-986142
140. RdRp Thumb-domain allosteric inhibitors
Compounds that dock to an allosteric pocket in the Thumb domain and reduce RdRp processivity; several repurposed/natural products show micromolar inhibition in biochemical assays64.
Possible treatments: lenrispodun, paritaprevir, saikosaponin B2, fenretinide
141. Mpro cleavage inside DMV lumen & pore-proximal processing
Super-resolution mapping places nsp5 (Mpro) predominantly inside double-membrane vesicles (DMVs), implying that polyprotein processing proceeds after DMV closure within the DMV lumen. Therapeutic concepts: inhibitors optimized for DMV access; agents that disrupt the Mpro-pore microenvironment47.
Possible treatments: nirmatrelvir, optimized Mpro macrocycles, pore-tethered Mpro inhibitors
142. HCV NS3/4A, NS5A, and NS5B polymerase/protein inhibition
Inhibitors developed for Hepatitis C, such as NS5A inhibitors and NS5B polymerase inhibitors, have potential cross-reactivity against SARS-CoV-2 replication machinery5.
Possible treatments: elbasvir, ledipasvir, sofosbuvir, velpatasvir
143. PLpro allosteric modulation
Targeting regulatory sites on the papain-like protease (PLpro) outside of the catalytic active site, the interface of the N-terminal ubiquitin-like (Ubl) domain69.
Possible treatments: engineered ubiquitin variants (UbVs), Ubl-catalytic domain interface disruptors
144. Spike-M protein interaction stabilization (ER retention)
Stabilizing the interaction between the Spike (S) protein cytoplasmic tail and the Membrane (M) protein to enhance S protein retention in the ERGIC. This prevents S protein trafficking to the cell surface, thereby reducing its availability to mediate cell-cell fusion (syncytia formation)21,31.
Possible treatments: S-M interaction stabilizers, small molecules enhancing M-mediated ER retrieval
145. ORF3a-VPS39 interaction inhibition (HOPS complex blockade)
The SARS-CoV-2 ORF3a protein binds the host VPS39 subunit of the HOPS complex, blocking autophagosome-lysosome fusion and preventing viral degradation. Small molecules binding the ORF3a cytosolic surface can disrupt this interface to restore autophagic flux and promote lysosomal degradation of viral components86.
Possible treatments: bictegravir, 4-(benzoylamino)benzoic acid
146. PLpro Zinc-finger disruption
Compounds that disrupt the structural zinc-finger motif of PLpro (essential for structural integrity) via metal ejection, intercalation, or coordination, thereby destabilizing the enzyme and inhibiting function70.
Possible treatments: zinc pyrithione, ebselen, Au-34, Ag-4b, disulfiram, Fragment 11
147. ORF3c mitochondrial modulation inhibition
The accessory protein ORF3c localizes to mitochondria and alters host metabolism by promoting a shift from glycolysis to fatty acid oxidation and OXPHOS. This increases reactive oxygen species (ROS) and inhibits autophagic flux; targeting ORF3c could restore metabolic homeostasis46.
Possible treatments: ORF3c inhibitors
148. Nsp13 RecA-2 and ZBD conformational rigidification
Compounds that bind to the viral helicase (nsp13) and induce structural rigidity in the RecA-2 and Zinc Binding Domains (ZBD). This stalls the helicase, preventing viral RNA unwinding and hindering its ability to bind to the Replication-Transcription Complex (RTC), without inhibiting ATPase activity or directly binding the nucleic acid substrate28.
Possible treatments: avasimibe, candesartan cilexetil, pranlukast
149. Viral -1 Programmed Ribosomal Frameshifting (-1 PRF) disruption
Targeting the highly conserved viral frameshift-stimulatory element (FSE) in the mRNA to alter -1 programmed ribosomal frameshifting efficiency. Disrupting this process impairs the translation switch from ORF1a to ORF1b, significantly reducing the synthesis of critical viral enzymes like RdRp88.
Possible treatments: merafloxacin, geneticin
Targeting Host Proteins/Factors
Replication inhibition mechanisms targeting host proteins/factors.
150. Nucleotide depletion
Inducing viral mutagenesis or depleting nucleotide pools.
Possible treatments: molnupiravir
151. GTP depletion
Inhibition of IMP dehydrogenase depleting guanosine nucleotides5.
Possible treatments: ribavirin, mycophenolate mofetil, azathioprine
152. Pyrimidine depletion
Inhibition of dihydroorotate dehydrogenase depleting pyrimidine nucleotides89.
Possible treatments: leflunomide, teriflunomide
153. Deoxyribonucleotide depletion
Inhibition of ribonucleotide reductase reducing deoxyribonucleotide pools.
Possible treatments: hydroxyurea
154. Glucose deprivation
Possible treatments: 2-deoxy-D-glucose, KAN0438757, 3PO
155. Amino acid depletion
Depletion of asparagine to inhibit viral protein synthesis.
Possible treatments: asparaginase
156. Iron chelation
Sequestration of iron to limit availability for viral replication.
Possible treatments: deferoxamine
157. Methyl donor depletion
Inhibition of S-adenosylmethionine synthesis impairing viral RNA methylation.
Possible treatments: cycloleucine
158. Glutamine antagonism
Inhibition of glutamine metabolism to reduce nucleotide precursors90.
Possible treatments: 6-diazo-5-oxo-L-norleucine
159. Cholesterol depletion
Reducing cellular cholesterol destabilises lipid rafts, impairs membrane fusion, and disrupts replication-organelle formation, limiting viral entry and assembly. Strategies include HMG-CoA-reductase inhibition and direct extraction of membrane cholesterol13,21,22,25,39,91 .
Possible treatments: simvastatin, atorvastatin, fluvastatin, hydroxypropyl-β-cyclodextrin, 25-hydroxycholesterol, imipramine, ceftanorine
160. Fatty acid-binding protein 4 (FABP4) inhibition
Disruption of FABP4, a host metabolic protein critical for the formation and function of SARS-CoV-2 replication organelles (double-membrane vesicles)22,92,93 .
Possible treatments: BMS309403, CRE-14
161. TrkA signaling inhibition
Suppressing the neurotrophin receptor TrkA interferes with SARS-CoV-2 RNA replication/assembly, producing multi-log viral reduction even when added hours after infection41.
Possible treatments: GW441756, AG879
162. CDK1-Cyclin B1 complex inhibition
SARS-CoV-2 depends on the host CDK1-Cyclin B1 complex to complete crucial steps of its replication cycle. Small-molecule CDK inhibitors force a G2/M cell-cycle arrest, sharply reducing viral RNA synthesis and protein production in vitro. Because CDK1 and Cyclin B1 are over-expressed in COVID-19 blood samples, they represent druggable host factors for broad-spectrum antiviral intervention94,95.
Possible treatments: roscovitine (seliciclib), flavopiridol, dinaciclib, SNS-032
163. Rho-GTPase / ROCK signaling inhibition
Viruses hijack Rho-family GTPases (RhoA, Rac1, Cdc42) and downstream ROCK/PAK/mDia kinases for actin- and microtubule-based trafficking. Inhibitors that block ROCK activity or prevent GTPase prenylation impair endocytosis, replication-organelle formation, and virion egress, and can potentiate innate antiviral signaling39,96.
Possible treatments: fasudil, GSK269962A, atorvastatin, Y-27632, NSC23766, ZCL278, simvastatin
164. Epigenetic chromatin-remodelling modulation
SARS-CoV-2 reprograms airway-epithelial transcription by activating host chromatin regulators - HDAC1/2/7, NCOR1, KAT2B (GCN5), cohesin (SMC3) and SWI/SNF components (PBRM1, SMARCA4). The resulting histone-acetylation and 3-D chromatin changes suppress interferon genes and create a replication-permissive state. Inhibiting these regulators with HDAC, EZH2 or SWI/SNF modulators restores antiviral transcription and sharply reduces viral yield in vitro5,57,66,68,97,98 .
Possible treatments: romidepsin, vorinostat, entinostat, tazemetostat, BRM/BRG1 inhibitors, valproic acid
165. G9a / EHMT2 lysine-methyltransferase inhibition
Blocking the histone H3K9 dimethyltransferase G9a (EHMT2) reverses SARS-CoV-2-driven chromatin silencing and m6A translational re-wiring, while secondarily impairing cathepsin-L maturation; the combined epigenetic effects suppress both viral entry and intracellular replication49,99.
Possible treatments: UNC0642, UNC0638, BIX01294, MS1262, UNC1999, tazemetostat, YX59-126
166. ER stress / UPR modulation
Pharmacologic tuning of the unfolded-protein response (BiP/HSPA5 induction, PERK-eIF2α signaling) restores ER homeostasis, curtails viral protein translation and blocks DMV biogenesis across coronaviruses34.
Possible treatments: thapsigargin, sephin1, TUDCA, 4-phenylbutyrate
167. AMPK activation & mTOR inhibition
Shifting cellular metabolism toward catabolism (AMPK) and dampening cap-dependent translation (mTOR blockade) depletes biosynthetic resources, suppressing SARS-CoV-2 RNA and protein output in vitro and in vivo5,17,22,100,101 .
Possible treatments: metformin, AICAR, berberine, rapamycin, everolimus, sirolimus
168. SLBP-mediated -1 programmed ribosomal frameshifting (-1 PRF) enhancement
Stem-loop-binding protein (SLBP) binds the SARS-CoV-2 -1 PRF pseudoknot through its R46/S94 RNA-binding pocket, boosts frameshifting and pp1ab synthesis; CRISPR or small-molecule disruption of SLBP-RNA interaction curtails replication102.
Possible treatments: siRNA-SLBP, antisense-gapmers, SLBP-RBD inhibitors
169. FUBP3-driven -1 PRF enhancement
Far-upstream element-binding protein 3 forms RNP complexes with SLBP and ribosomal proteins at the -1 PRF site to raise frameshifting; silencing restricts viral growth102.
Possible treatments: siRNA-FUBP3, RNA-interface disruptors
170. RPL10A/RPS3A/RPS14 ribosomal facilitation of -1 PRF
These ribosomal proteins co-localise with -1 PRF RNA and, when over-expressed, significantly increase frameshifting; their depletion suppresses replication, identifying them as host translation cofactors commandeered by SARS-CoV-2102.
Possible treatments: siRNA-RPL10A/RPS3A/RPS14, ribosomal-PPI modulators
171. Shiftless (SFL) inhibition of -1 PRF
Interferon-induced protein Shiftless competes at the -1 PRF site and lowers frameshifting, acting as an intrinsic restriction factor; boosting SFL or mimicking its mechanism can counter SLBP/FUBP3-mediated enhancement102.
Possible treatments: recombinant SFL, SFL-mRNA therapeutics
172. Mitochondrial bioenergetic preservation
Active SARS-CoV-2 main protease (Mpro) collapses oxidative phosphorylation, depolarizes or hyper-polarizes mitochondria and fragments their network; stabilizing the respiratory chain or blocking Mpro-mediated cleavage of mitochondrial proteins can maintain ATP production and limit virus-induced cell damage10,22,46,65,87,90,103,104 .
Possible treatments: SS-31 peptide, MitoQ, CoQ10, nicotinamide riboside, metformin, resveratrol, TOM70-agonist peptides, macrocyclic ORF9b-TOM70 blockers, VBIT-4, VBIT-12, VDAC1-neutralizing antibody, Mdivi-1
173. MAP2K1/2 (MEK1/2) inhibition
Suppressing the MAPK/ERK cascade by blocking MAP2K1/2 prevents phosphorylation of N, ORF9b and multiple NSPs, trimming viral RNA synthesis and dampening excess cytokine signaling5,34,42,98 .
Possible treatments: selumetinib, trametinib, cobimetinib, ATR-002, zapnometinib
174. DYRK1A depletion / degradation
Knocking out or destabilizing DYRK1A lowers ACE2/DPP4/ANPEP transcription and blocks double-membrane-vesicle formation, jointly impairing coronavirus entry and early RNA-replication steps42,105.
Possible treatments: DYRK1A-targeting PROTACs, CRISPR/siRNA-DYRK1A, nuclear-export mutants, harmalogs
175. TOM70 functional restoration
Stabilize or up-regulate TOM70 to counteract ORF9b-induced MAVS suppression, prevent lactate over-production and maintain antiviral oxidative phosphorylation103.
Possible treatments: 17-AAG analogues, celastrol derivatives, TOM70-agonist small molecules
176. VDAC1 inhibition & mitochondrial pore stabilisation
SARS-CoV-2 infection and pro-inflammatory cytokines drive VDAC1 over-expression, oligomerisation and plasma-membrane mis-targeting. The resulting ATP loss and mtDNA release fuel NLRP3/STING activation and macrophage dysfunction. Small-molecule or biologic VDAC1 blockers restore cellular bioenergetics, dampen chemokine release and correlate with reduced clinical severity104.
Possible treatments: VBIT-4, VBIT-12, VDAC1-neutralizing antibody, metformin, sulindac, hexokinase-mimetic peptides
177. PFKFB3 glycolytic flux inhibition
SARS-CoV-2 creates a high-flux glycolytic state; blocking the rate-limiting kinase PFKFB3 lowers fructose-2,6-bis-phosphate, curbs viral RNA synthesis, and dampens cytokine release90,95.
Possible treatments: KAN0438757, 3PO
178. Drp1-mediated mitochondrial fission inhibition
Excessive Drp1-driven fission fragments mitochondria, fuels ROS and cytokine surges in COVID-19; Mdivi-1 blocks Drp1 GTPase, restores Δψm and limits inflammation90.
Possible treatments: Mdivi-1
179. G3BP1/2 stress-granule potentiation
Boost the antiviral stress-granule pathway by up-regulating or mimicking Ras-GAP-SH3-domain-binding proteins-1/2 (G3BP1/2). Reinforced SGs sequester translation factors and viral RNAs, throttling SARS-CoV-2 protein synthesis. Double G3BP1/2 knockout increases viral titres, underscoring their overlapping antiviral role22,66,68,106 .
Possible treatments: imatinib, decitabine, SG-inducing eIF2α modulators, halofuginone, pateamine-A analogs, G3BP-stabilizing stapled peptides, small-molecule N-G3BP PPI disruptors
180. Host matrix-metalloproteinase (MMP) chelation
Chelation of the Zn²⁺ catalytic site on host MMPs limits MMP-assisted steps of SARS-CoV-2 replication and dampens downstream tissue damage5,67,107 .
Possible treatments: minocycline, doxycycline, tetracycline
181. Microtubule polymerisation inhibition
Disrupting α/β-tubulin dynamics impairs intracellular trafficking of viral components and lowers lung viral load; orally bio-available agents show potent protection in hamsters5,19,108,109 .
Possible treatments: sabizabulin, colchicine, vinblastine, vincristine
182. B0AT1 (SLC6A19) modulation
B0AT1 enhances ACE2 stability by assembling it into high-quality heterodimer structures. The ACE2-B0AT1 complex can simultaneously bind two spike proteins, significantly promoting viral recognition and infection1,20.
Possible treatments: SLC6A19 inhibitors, amino acid transport blockers
183. Calcineurin/NFAT pathway inhibition
Blocking the calcineurin-NFAT signaling pathway that is activated by viral Nsp1 through peptidyl-prolyl cis-trans-isomerases, contributing to immune activation1,44.
Possible treatments: cyclosporine A, tacrolimus
184. RNF2 (Ring Finger Protein 2) enhancement
Enhancing RNF2 expression or function to inhibit coronavirus replication. RNF2 is an E3 ubiquitin ligase that interacts with SARS-CoV-2 nucleocapsid protein and acts as an antiviral host factor. Overexpression reduces viral loads while knockdown increases viral replication73.
Possible treatments: RNF2 activators, ubiquitin ligase enhancers, RNF2-N protein interaction stabilizers
185. ARL15 (ADP ribosylation factor like GTPase 15) enhancement
Enhancing ARL15 expression or function to inhibit coronavirus replication. ARL15 is a small GTP-binding protein that interacts with SARS-CoV-2 nucleocapsid protein and acts as an antiviral host factor. Overexpression reduces viral loads while knockdown increases viral replication73.
Possible treatments: ARL15 activators, GTPase enhancers, ARL15-N protein interaction stabilizers
186. NEU1 sialidase inhibition
Host sialidase NEU1 removes terminal sialic acids from the coronavirus nucleocapsid (N) protein. Maintaining N sialylation lowers N-RNA binding and curbs replication; cell-permeable NEU1 inhibitors acting in the cytoplasm/lysosome (β-CoVs egress via lysosomes) suppress HCoV-OC43 and SARS-CoV-2 replication in vitro and in vivo74.
Possible treatments: Neu5Ac2en-OAcOMe (cell-permeable DANA analog), DANA/Neu5Ac2en derivatives with NEU1 selectivity
187. Class III PI3K (PIK3C3)-PI3P signaling
PIK3C3/PIK3R4 with VAC14 and WDR81/91 initiate endosomal maturation and early autophagy exploited by SARS-CoV-2 and seasonal HCoVs13.
Possible treatments: SAR405, PIK-III
188. TMEM41B-dependent autophagosome initiation
Conserved coronavirus dependency; early autophagy membrane remodeling supports replication organelle formation13,22.
Possible treatments: TMEM41B inhibitors
189. SREBP/SCAP/MBTPS1/2 lipid program
Master regulators of fatty acid/cholesterol synthesis required for coronavirus replication; disruption limits entry/replication13,17,45,66 .
Possible treatments: fatostatin, betulin, PF-429242
190. Lysosomal cholesterol export (NPC1/NPC2)
NPC1/NPC2 move cholesterol from lumen to membrane; required for CoV entry/fusion and trafficking13.
Possible treatments: U18666A, imipramine, 25-hydroxycholesterol
191. Sigma-1 receptor (SIGMAR1)-ER lipid microdomain support
SIGMAR1 interacts with nsp6 and organizes ER lipid microdomains used by positive-strand RNA viruses; modulators impact replication/host responses5,13,55 .
Possible treatments: fluvoxamine, naltrexone, PB28
192. eEF1A1 translation elongation factor
Host translation factor leveraged by SARS-CoV-2; inhibition shows potent antiviral activity in vitro and in vivo13,95,101 .
Possible treatments: plitidepsin
193. Caspase-6 inhibition / blockade of N-protein cleavage
Caspase-6 facilitates coronavirus replication by cleaving nucleocapsid (N) into IFN-antagonist fragments. Genetic knockdown/KO of CASP6 or pharmacologic inhibition reduces N cleavage, restores type-I IFN signaling, and suppresses replication; activity is post-entry and requires an intact IFN pathway75.
Possible treatments: dibenzoylmethane, Z-VEID-FMK, caspase-6 inhibitors
194. Aryl hydrocarbon receptor (AHR) antagonism
SARS-CoV-2 activates AHR, a proviral host factor that suppresses type-I IFN, promotes mucin hypersecretion, and drives inflammatory/metabolic dysregulation; antagonism restores antiviral signaling and may limit fibrosis57,58,110 .
Possible treatments: CH-223191, GNF351, BAY2416964
195. TiPARP/PARP7 inhibition (AHR effector)
AHR up-regulates TiPARP (PARP7), which supports coronavirus replication; dampening AHR-TiPARP signaling could reduce viral RNA output and restore IFN responses57.
Possible treatments: PARP7 inhibitors
196. TRMT1 (tRNA m2G/m22G) inhibition
3CLpro cleaves TRMT1 (Q530), and TRMT1 deficiency reduces intracellular viral RNA levels; pharmacologic TRMT1 inhibition may limit replication by depriving the virus of pro-replicative tRNA modifications66.
Possible treatments: TRMT1 inhibitors, RNA-binding aptamers that block TRMT1-tRNA interaction
197. Proteasome core (PSMB) inhibition
Predicted host factor PSMB2 (20S proteasome beta subunit) co-clusters with SARS-CoV-2-interacting proteins; inhibiting proteasome activity can impede viral protein turnover/replication and modulate downstream inflammation5,34,44 .
Possible treatments: carfilzomib
198. Replication-organelle dsRNA connector disruption
Thin dsRNA strands physically link DMVs and can tether DMV clusters to larger bodies; likely acting as conduits for spreading replication sites. Targeting their formation/trafficking could limit RO expansion47.
199. Membraneless dsRNA granule (viroplasm-like) dissolution
Large, rounded dsRNA granules lacking nsp3/nsp4 pores but decorated with nsp5/nsp8/nsp10/nsp12/nsp13 suggest phase-separated viral factories. Small-molecule condensate modulators or RNA-protein interface blockers may suppress replication47.
Possible treatments: 1, 6-hexanediol-class probes, condensate-modulating chemotypes, nsp-RNA interface inhibitors
200. Multi-layered body (MLB) clearance
Mpro inhibition induces persistent, multi-layered membrane stacks composed of uncleaved pp1a/pp1ab with nsp3 flanking each layer; MLBs can persist after drug washout and coincide with reinfection. Enhancing selective ER-phagy/MLB turnover or blocking nsp3/4 zippering may improve outcomes47.
Possible treatments: rapamycin, spermidine, ER-phagy activators, nsp3/4 ectodomain interaction blockers
201. Inositol monophosphatase (IMPase) inhibition
IMPase is a key enzyme for both de novo biosynthesis and recycling of cellular inositol. Inhibiting IMPase creates a chokepoint, limiting the availability of inositol and its derivatives (PtdIns, PPIns), which are essential for viral replication organelle formation and other processes hijacked by SARS-CoV-248,111.
Possible treatments: ivermectin, lithium, ebselen
202. Dihydrofolate reductase (DHFR) inhibition
Inhibition of dihydrofolate reductase, an enzyme essential for the synthesis of nucleotides, thereby depleting the building blocks required for viral RNA replication5.
Possible treatments: pyrimethamine
203. BRAF kinase inhibition
Targeting the host BRAF kinase, part of the MAPK/ERK signaling pathway, which can be hijacked by the virus to support its replication cycle. Inhibition may disrupt viral proliferation and modulate host inflammatory responses5.
Possible treatments: vemurafenib
204. Farnesyltransferase inhibition
Blocking the farnesylation (a type of prenylation) of host and potentially viral proteins, which is a critical post-translational modification for their membrane localization and function, thereby disrupting viral replication and assembly5.
Possible treatments: lonafarnib
205. Glucosylceramide synthase inhibition
Disruption of glycosphingolipid metabolism by inhibiting glucosylceramide synthase, which can alter the composition of lipid rafts and membranes of replication organelles, thereby impairing viral entry and replication5.
Possible treatments: miglustat
206. Glycogen synthase kinase 3 (GSK-3) inhibition
Inhibition of GSK-3, a key regulator of numerous cellular processes including inflammation, apoptosis, and metabolism, which can be hijacked by SARS-CoV-2 for replication5,62,112-114 .
Possible treatments: lithium, kenpaullone
207. Phosphoinositide 3-kinase (PI3K) / PIK3CA inhibition
Blocking the PI3K/AKT/mTOR signaling pathway (specifically targeting PIK3CA), which is crucial for cell survival and autophagy regulation, and may be hijacked by SARS-CoV-2 to promote inflammation5,23.
Possible treatments: duvelisib, linolenic acid, pistagremic acid
208. Poly (ADP-ribose) polymerase (PARP) inhibition
Inhibition of PARP enzymes, which are involved in DNA repair and inflammatory signaling. PARP inhibitors may exert antiviral effects by modulating the host response and limiting virus-induced cellular stress5,77.
Possible treatments: rucaraparib
209. Broad tyrosine kinase inhibition
Inhibition of multiple host cell tyrosine kinases that regulate signaling pathways essential for viral entry, replication, and the induction of pro-inflammatory cytokines5.
Possible treatments: entrectinib, nilotinib, vandetanib
210. Pro-viral host protein domains (COMM, PX, RRM)
Specific host protein domains have been identified as critical for SARS-CoV-2 pro-viral activity, including the COMM (Copper metabolism MURR1) domain, Phox homology (PX) domains, and RNA recognition motifs (RRM). Targeting these domains may disrupt host factor support for viral replication56.
Possible treatments: COMM domain inhibitors, PX domain antagonists, RRM-targeting small molecules
211. TRMT1 (tRNA m2G/m22G) inhibition
The viral main protease (3CLpro/Mpro) cleaves the host tRNA methyltransferase 1 (TRMT1), which disrupts proper tRNA folding and global protein synthesis. Since viral replication is dependent on the host's translational machinery, pharmacologic inhibition of TRMT1 may limit the resources available for viral protein production68.
Possible treatments: TRMT1 inhibitors, RNA-binding aptamers that block TRMT1-tRNA interaction
212. HSF1 inhibition to reduce replication & stress-adaptive transcription
Human coronaviruses activate HSF1; HSF1 phosphorylation (e.g., Ser326) drives a stress program that can aid replication and intersect with NF-κB/STAT3; inhibiting HSF1 may blunt viral fitness and inflammatory stress58.
Possible treatments: HSF1 inhibitors (e.g., KRIBB11-class)
213. CRL2ZYG11B (Cullin-2 E3 ligase) inhibition
ORF10 hijacks the ZYG11B substrate adaptor to engage the CRL2 E3 ligase complex, increasing its activity to degrade IFT46, which results in ciliary dysfunction87.
Possible treatments: pevonedistat (MLN4924), other NEDD8-activating-enzyme inhibitors, ZYG11B-substrate PPI disruptors
214. CFL1/cofilin-1-driven actin remodeling
Cofilin-1 regulates actin turnover that viruses co-opt for entry, trafficking, and egress; elevated/diagnostic CFL1 supports targeting cofilin-LIMK signaling or actin-endocytosis dynamics to curb replication and temper dysregulated immune-cell motility91.
Possible treatments: LIMK inhibitors (e.g., LIMKi3), actin-cofilin modulators (experimental)
215. 5' isomiR miR-4485-3p|+1 - repression of cell-cycle/translation/metabolism
A host microRNA variant (miR-4485-3p+1) that SARS-CoV-2 induces at 24 hours post-infection. The virus appears to use this isomiR to shut down key host pathways, including the cell cycle, protein translation, and metabolism, helping the virus replicate more effectively. A therapeutic antagomir (inhibitor) could block this isomiR, preventing the virus from hijacking these essential host processes95.
Possible treatments: miR-4485-3p|+1 mimic, miR-4485-3p|+1 antagomir, chemically stabilized oligos
216. Drosha (RNase-III) non-canonical function inhibition
Blocking the host protein Drosha, which is required for efficient SARS-CoV-2 replication. Infection by SARS-CoV-2 induces proteolytic cleavage of full-length Drosha into P140 and P25 isoforms and causes its translocation from the nucleus to the cytoplasm. Ablation of Drosha significantly reduces viral genomic and sub-genomic RNA levels, suggesting a non-canonical, pro-viral role113.
Possible treatments: small-molecule Drosha activity/processing inhibitors
217. COPI-Spike binding enhancement (ER retrieval)
Enhancing the binding of the host COPI complex to the ER retrieval motif in the Spike protein cytoplasmic tail. Increased COPI binding promotes intracellular retention of Spike, reducing its trafficking to the cell surface and subsequent cell-cell fusion (syncytia formation)21.
Possible treatments: COPI binding agonists, Spike-COPI interaction stabilizers
218. VMP1-mediated DMV formation
Vacuole Membrane Protein 1 (VMP1) works in concert with TMEM41B to facilitate the "zippering" of ER membranes, converting them into closed spherical double-membrane vesicles (DMVs) essential for the viral replication organelle22.
219. HDAC1-mediated viral protein acetylation
HDAC1 is recruited to regulate the acetylation state of viral proteins, which influences nuclear retention and enhances viral replication efficiency22.
Possible treatments: valproic acid
220. Ribosome biogenesis factors (SBDS & SPATA5)
Host factors SBDS and SPATA5, involved in ribosome biogenesis, are identified as broad-spectrum host dependency factors required for efficient viral protein synthesis and replication22.
221. TMEM41B/VMP1-mediated DMV formation inhibition
TMEM41B mediates nsp3-nsp4 binding to initiate ER membrane zippering for double-membrane vesicle (DMV) formation. VMP1 is subsequently required to convert these membranes into closed spherical DMVs that serve as viral replication organelles for coronaviruses22.
Possible treatments: TMEM41B inhibitors, VMP1 inhibitors
222. Liquid-liquid phase separation (LLPS) condensate disruption
Disrupting the multivalent interactions, ionic environment, or post-translational modifications (e.g., phosphorylation) that drive the formation of viral replication organelles and inclusion bodies via LLPS. Targeting these "reaction crucibles" can destabilize viral factories22.
Possible treatments: 1, 6-hexanediol-class probes, condensate-disrupting small molecules, kinase inhibitors affecting condensate phosphorylation
223. HSP90AA1 inhibition
HSP90AA1 is a molecular chaperone that ensures proteostasis; its inhibition disrupts SARS-CoV-2 virion assembly, suppresses viral replication, and mitigates virus-induced pyroptosis23,82.
Possible treatments: pistagremic acid, linolenic acid, 1-dehydro-6-gingerol
224. ACE2 phosphorylation and exosomal propagation inhibition
Spike protein enhances viral susceptibility by activating ACE2 phosphorylation, inhibiting its degradation, and promoting exosomal ACE2 propagation, thereby increasing host susceptibility to infection26.
Possible treatments: ACE2 phosphorylation inhibitors, exosome biogenesis inhibitors
225. ZO-1 (TJP1) PDZ2 interaction blockade
Inhibition of the protein-protein interaction (PPI) between the SARS-CoV-2 Envelope (E) protein's C-terminal PDZ-binding motif (PBM) and the host ZO-1 PDZ2 domain. This interaction disrupts tight junctions, compromises epithelial barriers, and fuels cytokine storms115.
Possible treatments: C19 (quinoline derivative), C6, C20, C35, C29, C32
226. DGAT1 (diacylglycerol O-acyltransferase 1) inhibition
SARS-CoV-2 upregulates DGAT1 expression via SCAP/SREBP-1 signaling to drive de novo lipogenesis in the smooth endoplasmic reticulum. The resulting lipid droplets serve as viral replication platforms and assembly sites. DGAT1 inhibition reduces lipid droplet accumulation and may limit viral replication organelle formation17,45.
Possible treatments: pradigastat, AZD7687, PF-04620110, T863
227. SF-1 (NR5A1) steroidogenic pathway preservation
SARS-CoV-2 infection downregulates steroidogenic factor-1 (SF-1/NR5A1) expression. Preserving SF-1 function may protect steroidogenic capacity and reduce virus-induced hypogonadism45.
Possible treatments: SF-1 agonists, AMPK modulators
228. Lipid droplet replication platform disruption
SARS-CoV-2 triggers host lipid metabolism, inducing the accumulation of lipid droplets and "spirally arranged cisternae" (SAC) derived from the ER. The virus upregulates Srebp1, Dgat-1, and Scarb1 to drive cholesterol uptake and lipogenesis, creating a platform for viral replication. Targeting these pathways disrupts the replication organelle biogenesis17,45.
Possible treatments: fatostatin, betulin, DGAT-1 inhibitors (pradigastat), SR-B1 antagonists (BLT-1)
229. SIRT3 mitochondrial deacetylation restoration
SIRT3 is significantly downregulated in SARS-CoV-2 infected cardiomyocytes. As a key mitochondrial NAD+-dependent deacetylase, it regulates oxidative stress and inhibits ferroptosis; restoring SIRT3 activity preserves mitochondrial function and prevents cell death62.
Possible treatments: honokiol, resveratrol, SIRT3 activators
230. DDX3X RNA helicase inhibition
The host DEAD-box RNA helicase DDX3X physically interacts with the SARS-CoV-2 Nucleocapsid to enhance viral dsRNA binding and RNP packaging. DDX3X is also exploited to suppress innate immune signaling. Inhibiting DDX3X helicase activity blocks these pro-viral functions76.
Possible treatments: RK-33
231. HSP70-NSP13 interaction inhibition
Computational modeling indicates that host HSP70 forms a remarkably rigid and compact complex with the SARS-CoV-2 helicase (NSP13), stabilizing the viral protein. Disrupting this chaperone-client interaction could impair viral replication82.
Possible treatments: HSP70 inhibitors, protein-protein interaction disruptors
232. HSP40 (DNAJ)-NSP13 interaction inhibition
HSP40 functions as a co-chaperone that binds SARS-CoV-2 NSP13 via specific polar contacts. Targeting this interface may prevent the delivery of the viral helicase to the HSP70 folding machinery82.
Possible treatments: HSP40 inhibitors, J-domain blockers
233. Fibronectin Receptor alpha (FNRA/ITGA5) modulation
FNRA (Integrin alpha-5) is induced by SARS-CoV structural proteins. FNRA localizes to lipid rafts and contributes to the cytoskeletal anchoring and membrane dynamics necessary for efficient viral assembly39.
Possible treatments: ATN-161, volociximab, peptide inhibitors
234. Intracellular Vimentin (VIM) cytoskeletal disruption
Distinct from extracellular vimentin involved in entry, intracellular vimentin is upregulated by viral structural proteins and associates with lipid rafts. It facilitates the cytoskeletal remodeling required to support virion morphogenesis and budding at the ERGIC39.
Possible treatments: withaferin A, fiVe1
235. CDKN1A (p21) modulation
SARS-CoV structural proteins upregulate CDKN1A (p21). p21 regulates the cell cycle; its manipulation arrests cell growth, potentially creating a favorable metabolic environment for viral protein synthesis and assembly39.
Possible treatments: UC2288, sorafenib
236. Kif11 (Eg5) kinesin inhibition
Kinesin Family Member 11 (Kif11/Eg5) is a top hub gene in the lung transcriptomic network of SARS-CoV-2 infection and is involved in spindle formation and cell cycle regulation. Dysregulation contributes to pathogenesis, and inhibitors may limit viral propagation or associated tissue damage116.
Possible treatments: filanesib, ispinesib, monastrol, dimethylenastron
237. Aurora Kinase B (Aurkb) inhibition
Aurkb is a key mitotic kinase identified as a central hub gene in infected lung tissue and regulates chromosomal segregation and cytokinesis. High expression correlates with severe COVID-19, suggesting potential for kinase inhibitors to modulate virus-induced cell cycle dysregulation116.
Possible treatments: barasertib, AZD1152, hesperidin, ZM447439
238. Ube2c (Ubiquitin Conjugating Enzyme E2 C) inhibition
Identified as a top 10 hub gene in SARS-CoV-2 infection, Ube2c is essential for the destruction of mitotic cyclins. Upregulation in severe infection links the ubiquitin-proteasome system to viral manipulation of the host cell cycle116.
Possible treatments: TZ9, gliotoxin
239. Galectin-3 (LGALS3) inhibition
Galectin-3 is a beta-galactoside-binding lectin upregulated in the heart and brain during SARS-CoV-2 infection. It facilitates viral attachment, drives pro-inflammatory cytokine secretion (IL-6, TNF-α), promotes fibrosis, and is linked to post-COVID sequelae and cancer risks55.
Possible treatments: belapectin, olitigaltin, lactose anhydrous, davanat, modified citrus pectin, GB0139
240. CDK2 / Cyclin D1/E1 (G1/S transition) inhibition
SARS-CoV-2 NSP6 dysregulates the G1/S cell cycle transition in brain tissue by influencing hub genes CDK2, CCND1, and CCNE1. Targeting these kinases may prevent viral hijacking of the cell cycle and reduce neurodegenerative or proliferative sequelae55.
Possible treatments: palbociclib, raltitrexed, lapatinib, methotrexate, acetaminophen, abemaciclib, ribociclib
241. ATPase 13A3 (ATP13A3) interaction blockade
ATP13A3 is a polyamine transporter and host hub gene that directly interacts with SARS-CoV-2 NSP6 in the brain and heart. Modulating its activity or its interaction with NSP6 may disrupt viral replication organelles and polyamine homeostasis55.
242. PARP12/PARP13 (ZAP) - NMD axis activation
PARP12 and PARP13 are zinc-finger host antiviral factors that bind SARS-CoV-2 genomic and subgenomic RNAs. They recruit the Nonsense-Mediated Decay machinery to degrade viral RNA. While the virus induces their expression, enhancing their activity via agonists restricts replication77,88.
Possible treatments: PARP12 agonists, PARP13 agonists
243. Nonsense-mediated mRNA decay (NMD) enhancement
The NMD pathway acts as an intrinsic antiviral mechanism that recognizes and degrades SARS-CoV-2 RNAs. The virus actively suppresses UPF1/UPF2 expression and function to enhance viral RNA stability. Therapeutic strategies that restore or boost NMD activity can limit viral replication77,101.
Possible treatments: NMD activators
244. METTL3 RNA m6A methyltransferase inhibition
Inhibition of the host METTL3 RNA m6A methyltransferase reduces m6A modification on viral RNA and downregulates the m6A modification and expression of proviral host entry factors117.
Possible treatments: onvansertib, vilazodone, STM2457
245. ACAT (Acyl-CoA:cholesterol acyltransferase) inhibition
Inhibiting the host ACAT enzyme alters lipid metabolism, which can suppress viral replication and boost antiviral T-cell activity. Some ACAT inhibitors exhibit multifaceted mechanisms, including direct inhibition of the viral nsp13 helicase activity and perturbation of viral replication foci28.
Possible treatments: avasimibe
246. DDX1 RNA helicase interaction inhibition
The host RNA helicase DDX1 directly interacts with the phosphorylated serine-arginine (SR) region of the SARS-CoV-2 Nucleocapsid (N) protein to facilitate viral transcription and replication. Disrupting this interface with competitive phosphorylated SR peptides prevents N-DDX1 complex formation and actively destabilizes established complexes114.
Possible treatments: phosphorylated SR peptides, phosphomimetic SR peptides (9DR)
247. Serine/arginine-rich protein kinase 1 (SRPK1) inhibition
Host kinases such as SRPK1 progressively phosphorylate the SR region of the SARS-CoV-2 Nucleocapsid protein. Inhibition of SRPK1 diminishes N protein phosphorylation, which disrupts liquid-liquid phase separation, impairs ribonucleoprotein assembly, and blocks the recruitment of pro-viral host factors114.
Possible treatments: SRPK1 inhibitors
248. Peptidyl-arginine deiminase 4 (PAD4) inhibition
SARS-CoV-2 infection upregulates host PAD4, leading to aberrant protein citrullination that supports viral genome replication and protein synthesis post-entry. PAD4-specific inhibitors potently suppress viral replication93.
Possible treatments: GSK199, GSK484, BB-Cl-amidine, Cl-amidine
249. FYCO1-mediated autophagosome transport modulation
FYCO1 is a host protein essential for autophagosome transport along microtubules. Multi-omics and conditional genetic analyses identify FYCO1 as a COVID-19-specific risk gene, distinct from general respiratory diseases, highlighting the critical role of targeted autophagy-lysosomal trafficking in viral pathology40.
Possible treatments: autophagy modulators, microtubule-autophagosome trafficking enhancers, FYCO1-targeted compounds
250. DPP9 (dipeptidyl peptidase 9) shared COVID-19/IPF biology
DPP9 is identified as a validated shared locus between COVID-19 and IPF with concordant effects across multiple COVID-19 phenotypes (A2, B2, C2). Supported by SNP-level colocalization and gene-level evidence from spTWAS40.
Possible treatments: DPP9 inhibitors
251. ARF1-mediated ERGIC assembly disruption
The viral M protein relies on the host ADP-ribosylation factor 1 (ARF1) pathway for proper localization at the ER-Golgi intermediate compartment (ERGIC) during virion assembly. Inhibitors targeting ARF1 disrupt the colocalization of ARF1 and the M protein, thereby weakening virion assembly and suppressing viral replication31.
Possible treatments: brefeldin A, golgicide A, PEP17
252. HSP70-M protein interaction inhibition
Host heat shock protein 70 (HSP70) is robustly overexpressed during infection and interacts directly with the viral M protein. This interaction accelerates viral replication and facilitates the release of pro-inflammatory cytokines, making the disruption of this complex a viable target for restricting viral assembly and downstream inflammation31.
Possible treatments: HSP70 inhibitors
253. M protein STX18-ATG14 lipophagy exploitation
The SARS-CoV-2 M protein promotes viral replication by disrupting syntaxin 18 (STX18) to induce ATG14-mediated lipid phagocytosis (lipophagy), combined with its ability to degrade the antiviral effector RSAD2 (viperin). This dual mechanism hijacks host lipid turnover pathways to support viral assembly while simultaneously disabling an interferon-stimulated restriction factor31.
Possible treatments: STX18 stabilizers, ATG14 lipophagy inhibitors, RSAD2 degradation blockers
254. Aurora A (AurA)-HDAC6 ciliary disassembly inhibition (M protein-mediated)
Multiple coronaviruses interact with host Aurora A kinase and histone deacetylase 6 (HDAC6) via their M proteins, inducing primary cilium disassembly during early infection. Distinct from HDAC6 roles in capsid uncoating, this targets M protein-driven ciliary loss that likely facilitates viral spread in ciliated epithelia31.
Possible treatments: alisertib (MLN8237), barasertib, Aurora A inhibitors, tubacin, ricolinostat, HDAC6 selective inhibitors
255. Sphingosine kinase 2 (SK2) inhibition
Inhibition of sphingosine kinase 2 suppresses viral replication and inhibits the hyperinflammatory response to viral infection17.
Possible treatments: opaganib
256. Fatty acid beta-oxidation modulation
Viruses including SARS-CoV-2 modulate mitochondrial fatty acid beta-oxidation via CPT1/CPT2 (carnitine palmitoyltransferase) to alter energy utilization and support viral replication. Inhibiting or redirecting beta-oxidation can starve viral replication of energy substrates while potentially enhancing immune cell metabolic fitness, as exhausted T cells in chronic viral infections exhibit impaired mitochondrial fatty acid oxidation17.
Possible treatments: etomoxir, perhexiline, trimetazidine, ranolazine
257. Ceramide/sphingomyelin accumulation for viral assembly
Viral infection induces accumulation of ceramide and sphingomyelin lipids that play a role in the assembly of viral particles. Specific sphingolipid species are enriched in viral particles, and very-long-chain fatty acid and sphingolipid synthesis supports viral RNA replication and quasi-enveloped virus release. Disrupting sphingolipid biosynthesis or ceramide accumulation can impair virion assembly17.
Possible treatments: myriocin, fumonisin B1, GW4869, desipramine, amitriptyline
258. Fatty acid synthase (FASN) inhibition
FASN is a key lipogenic enzyme upregulated during viral infection through SREBP activation and mTOR signaling. Viruses including SARS-CoV-2, HCV, and influenza increase FASN activity to generate fatty acids essential for viral envelope formation, replication compartment biogenesis, and lipid droplet accumulation. FASN inhibition depletes the de novo fatty acid supply required across multiple stages of the viral life cycle17.
Possible treatments: TVB-2640 (denifanstat), orlistat, cerulenin, C75, GSK2194069
259. CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) modulation
CFTR dysfunction creates a non-permissive intracellular environment for SARS-CoV-2. Impaired CFTR function disrupts intracellular chloride and bicarbonate transport, leading to chronic organelle hyperacidification, defective unfolded protein response (UPR), and impaired autophagy118.
Possible treatments: CFTR(inh)-172, GlyH-101
260. HuR (ELAVL1) RNA-binding protein inhibition
Inhibiting the host RNA-binding protein HuR (human antigen R / ELAVL1), which binds to the SARS-CoV-2 genomic 5'-UTR near the C241 site and recruits PTB (PTBP1) to aid ribosome loading and enhance the translation of viral non-structural proteins63.
Possible treatments: suramin, ASO5
261. PTB (PTBP1) polypyrimidine tract-binding protein targeting
Targeting the host polypyrimidine tract-binding protein (PTB/PTBP1), which is recruited by HuR to the viral genomic 5'-UTR. PTB directly binds the 5'-UTR to aid ribosome loading and promote translation of viral non-structural proteins essential for the replication cycle63,101.
Possible treatments: siRNA-PTB
262. ZAP-S (zinc-finger antiviral protein) stabilization & -1 PRF inhibition
The short isoform of the host zinc-finger antiviral protein (ZAP-S) acts as an intrinsic restriction factor by suppressing -1 programmed ribosomal frameshifting (-1PRF). Small molecules can directly bind ZAP-S and enhance its thermal stability. This disrupts -1PRF, which is critical for translating the ORF1b sequence and synthesizing viral polyproteins like RNA-dependent RNA polymerase (RdRp)88.
Possible treatments: lycorine, lycorine derivatives (compound 7)
263. LARP1 (La-related protein 1) inhibition
LARP1 is hijacked by SARS-CoV-2 to enhance viral replication, binding the 5' UTR of the viral genome and regulating cap-dependent translation of TOP mRNAs downstream of mTORC1101.
Possible treatments: sapanisertib, sirolimus, rapamycin, ulocuplumab
264. eIF4A1 (eukaryotic translation initiation factor 4A1) inhibition
eIF4A1 is an ATP-dependent DEAD-box RNA helicase that unwinds structured 5' UTRs to enable cap-dependent translation initiation. SARS-CoV-2 and other RNA viruses co-opt eIF4A1 for efficient viral protein synthesis101.
Possible treatments: zotatifin (eFT226), rocaglamide, RocB, triparanol
265. eIF4H translation initiation factor inhibition
eIF4H stimulates the RNA helicase activity of eIF4A during cap-dependent translation initiation. Zotatifin (eFT226) clamps eIF4A onto specific mRNA polypurine motifs and has been advanced into clinical evaluation for COVID-19101.
Possible treatments: zotatifin (eFT226)
266. eEF1G (eukaryotic elongation factor 1 gamma) inhibition
eEF1G is a subunit of the eEF1 complex that delivers aminoacyl-tRNAs to the ribosome during translation elongation. Distinct from eEF1A1, eEF1G is a conserved host factor across SARS-CoV-2, IAV, ZIKV, and DENV RNA interactomes101.
Possible treatments: idelalisib, suramin, trifluralin
267. Nucleolin (NCL) inhibition
Nucleolin is a multifunctional RNA-binding protein involved in ribosome biogenesis, RNA processing, and interferon signaling. NCL is a conserved hub across SARS-CoV-2, IAV, ZIKV, and DENV RNA interactomes and has shown promise as a broad-spectrum antiviral target; small-molecule modulators or interface disruptors of NCL can block viral RNA-protein interactions101.
Possible treatments: mercaptopurine (Purinethol), NCL-targeting aptamers (AS1411)
268. ILF3 (Interleukin Enhancer Binding Factor 3 / NF90) modulation
ILF3/NF90 is a double-stranded RNA-binding protein that participates in the establishment of the type I interferon antiviral program and regulates viral RNA stability and translation. ILF3 is a conserved host factor across SARS-CoV-2, IAV, ZIKV, and DENV RNA interactomes101.
Possible treatments: selumetinib, MLN4924 (pevonedistat), cyclosporine, triparanol
269. hnRNP A1 / hnRNP K RNA-binding protein inhibition
Heterogeneous nuclear ribonucleoproteins A1 and K are conserved RNA-binding proteins recruited by multiple RNA viruses to facilitate viral RNA splicing, stability, translation, and packaging101.
Possible treatments: toremifene, camptothecin, paclitaxel, artenimol (dihydroartemisinin)
270. DDX39B / DDX42 DEAD-box helicase inhibition
DDX39B and DDX42 are DEAD-box RNA helicases that participate in mRNA export, splicing, and ribonucleoprotein remodeling. Both are conserved host factors across SARS-CoV-2, IAV, ZIKV, and DENV RNA interactomes101.
Possible treatments: rocaglamide, RocB, capsaicin, tideglusib, losmapimod, savolitinib, rivoceranib, AMG-208, nilotinib, erlotinib, sorafenib
271. NPM1 (Nucleophosmin) inhibition
Nucleophosmin (NPM1/B23) is a nucleolar chaperone that shuttles between nucleus and cytoplasm and contributes to ribosome biogenesis, RNA processing, and viral RNP assembly. NPM1 is a conserved host factor across SARS-CoV-2, IAV, ZIKV, and DENV RNA interactomes101.
Possible treatments: toremifene, mercaptopurine, imatinib, triparanol
272. NONO (Non-POU domain-containing octamer-binding protein) modulation
NONO is a paraspeckle component RNA-binding protein that functions in DNA repair, mRNA splicing, and innate antiviral RNA sensing. NONO is a conserved host factor across SARS-CoV-2, IAV, ZIKV, and DENV RNA interactomes101.
Possible treatments: auranofin
273. KHDRBS1 (Sam68) RNA-binding modulation
KHDRBS1/Sam68 is a KH-domain RNA-binding protein that regulates alternative splicing, mRNA stability, and signal transduction. It is a conserved host factor across SARS-CoV-2, IAV, ZIKV, and DENV RNA interactomes101.
Possible treatments: triparanol
274. Conserved ribosomal protein (RPL3/RPL8/RPL15/RPS2/RPS6/EIF3F) targeting
Multiple ribosomal proteins (RPL3, RPL8, RPL15, RPS2, RPS6) and the translation initiation factor subunit EIF3F are conserved host factors across SARS-CoV-2, IAV, ZIKV, and DENV RNA interactomes, reflecting universal viral dependence on the host ribosome101.
Possible treatments: anisomycin, omacetaxine (Synribo), artenimol (dihydroartemisinin), toremifene
Viral Egress & Budding Inhibition
Mechanisms that prevent or delay release of newly-formed virions from infected cells.
275. BST2/tetherin potentiation & viral-antagonist inhibition
Host restriction factor BST2 tethers nascent virions; priming BST2 expression or blocking viral antagonists (ORF7a, ORF3a, Omicron spike) traps particles on the cell surface, curbing spread22,43,47 .
Possible treatments: IFN-β priming, BST2 agonist peptides, small-molecule ORF7a-BST2 interface blockers
276. Lysosome-mediated egress blockade & large virus-containing vesicle traffic
M and S1 accumulate in lysosomes and LAMP1-negative vesicles; clustered, hollow rings indicate high virion load pre-egress. Inhibiting lysosomal exocytosis/vesicle traffic could curb release22,47.
Possible treatments: TRPML1 inhibitors, lysosomal exocytosis blockers, PIKfyve-pathway modulators
277. CRM1 (XPO1) nuclear export inhibition
Viruses exploit the host CRM1 (Exportin-1) pathway to transport viral ribonucleoprotein (vRNP) complexes or RNA genomes from the nucleus to the cytoplasm for assembly22.
Possible treatments: selinexor, verdinexor
278. NXF1-mediated mRNA export inhibition
The NXF1 host system is hijacked for the nuclear export of viral mRNAs; targeting this pathway prevents viral transcripts from reaching the cytoplasm for translation22.
Possible treatments: tapinarof
279. Acid Sphingomyelinase (ASM) inhibition
ASM activity leads to the clustering of phosphatidylserine (PS) on the plasma membrane inner leaflet, creating a specific lipid microenvironment or "launching pad" required for efficient viral budding22,108.
Possible treatments: fendiline, imipramine
280. Neutral Sphingomyelinase 2 (nSMase2) inhibition
nSMase2 regulates membrane lipid composition and curvature. Inhibiting this enzyme disrupts the formation of lipid rafts/microdomains necessary for viral assembly and egress22.
Possible treatments: nSMase2 inhibitors
281. Calcium-dependent EV release inhibition
Calcium influx is a critical upstream regulator of extracellular vesicle (EV) release. Blocking this pathway prevents the egress of EVs containing viral RNA/replicons, thereby limiting virion-independent transmission108.
Possible treatments: calpeptin
Host Immune Modulation
Mechanisms that modulate the host immune response to enhance antiviral activity or reduce immunopathology.
282. Cytokine storm suppression
Anti-inflammatory agents target cytokine pathways (IL-1/IL-6/JAK-STAT/TNF-α/complement) or inflammasomes to mitigate excessive inflammation5,9,10,18,29,34,38,44,59,85,104,109,112,116,119-125 .
Possible treatments: dexamethasone, methylprednisolone, tocilizumab, sarilumab, baricitinib, ruxolitinib, anakinra, canakinumab, infliximab, adalimumab, colchicine, lenzilumab, eculizumab, NE-52-QQ57, collagen-PVP, pirfenidone, MSC therapy, MSC-derived exosomes, budesonide, hydrocortisone, ciclesonide, artesunate
283. Interferon (type I/II) signaling enhancement
Boosting type I/II interferons or upstream sensors (e.g., STING, RIG-I) to stimulate antiviral gene expression10,21,22,40,58,66,85,112 .
Possible treatments: interferon-beta, interferon-alpha, interferon-gamma, nitazoxanide
284. Pegylated interferon-λ receptor agonists
Peg-IFN-λ engages IFNLR1 on respiratory epithelium, amplifies local ISGs with minimal systemic inflammation10,40,58,126 .
Possible treatments: peginterferon λ-1a, peg-IFN-β-1a
285. Adaptive immune enhancement
Possible treatments: convalescent plasma, monoclonal antibodies, intravenous immunoglobulin (IVIG), thymosin alpha 1, interleukin-7, interleukin-2, nivolumab
286. Innate immune stimulation
Activating innate immunity via PRRs (TLRs, RIG-I, STING) or antiviral effector mechanisms5,26,85,106,127 .
Possible treatments: imiquimod, resiquimod, polyinosinic-polycytidylic acid (poly I:C), monophosphoryl lipid A, CpG oligonucleotides, NOD1/2 agonists
287. Zinc supplementation
Zinc deficiency correlates with severity. Intracellular zinc availability is buffered by metallothioneins and modulates redox status, antiviral immunity, and viral RNA polymerase function24,51.
Possible treatments: zinc sulfate, zinc gluconate
288. Selenium supplementation
Enhancing antioxidant defenses and potentially inhibiting viral replication51.
Possible treatments: sodium selenite, selenomethionine
289. Micronutrient supplementation for immune system support
Additional vitamins, minerals, and cofactors essential for immune cell function and signaling128.
Possible treatments: vitamin A, vitamin C, vitamin D, vitamin E, vitamin B6, vitamin B12, zinc, selenium, iron, copper, magnesium, vitamin K
290. Immune regulation
Modulating regulatory immune cells (e.g., Tregs) or checkpoint pathways to balance inflammation129.
Possible treatments: low-dose interleukin-2, abatacept, sirolimus
291. NPY-Y1 receptor antagonism
Inhibition of the neuropeptide Y sub-receptor 1 (NPY-Y1) to modulate inflammatory responses. NPY-Y1 receptor antagonists disrupt the NPY-NPY-Y1 receptor cascade, which shows strong correlations with inflammatory cytokines and VEGF expression, which may help regulate cytokine balance and reduce pulmonary edema associated with severe COVID-19130.
Possible treatments: BIBO3304, BIBP3226
292. cGAS-STING agonists
Possible treatments: DMXAA, 2'3'-cGAMP, ADU-S100, diABZI
293. GM-CSF pathway inhibition
Neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) or its receptor blunts monocyte/macrophage-driven cytokine storm and lung injury in severe COVID-1940,127,131,132 .
Possible treatments: mavrilimumab, lenzilumab, otilimab, sargramostim
294. IL-17 axis blockade
Blocking interleukin-17 signaling counters ORF8-mediated IL-17 mimicry and downstream NF-κB activation, reducing neutrophil recruitment and pulmonary damage16,57,58,85,98,123,127 .
Possible treatments: secukinumab, ixekizumab, brodalumab, L-asparaginase, apigenin, amygdalin, phytic acid, kaempferol, candesartan
295. Mast-cell stabilisation & IgE-axis inhibition
Stabilizing mast cells or neutralizing free IgE to quell IL-4/IL-13-mediated “IgE storm” that accompanies severe COVID-19 in some variants9.
Possible treatments: omalizumab, cromolyn sodium, ketotifen, rupatadine
296. Short-chain fatty-acid supplementation
Exogenous butyrate / propionate / acetate activate GPR43/GPR109A, damp NLRP3 inflammasome, expand T-regs and boost type I IFN signaling, thereby curbing lung injury and viral load128.
Possible treatments: sodium butyrate, tributyrin, propionate pro-drugs
297. GPR183 (EBI-2) antagonism
Blocking the oxysterol-sensing GPCR GPR183 curbs chemotactic recruitment of inflammatory monocytes/macrophages into the airways while sparing early IFN signaling, easing lung inflammation131.
Possible treatments: NIBR-189, GSK 682753A
298. GM-CSF for alveolar-macrophage function
Nebulized rh-GM-CSF re-educates dysregulated lung macrophages, improves gas exchange and promotes viral clearance without provoking cytokine-release syndrome40,131.
Possible treatments: sargramostim, rh-GM-CSF
299. SYK inhibition
Inhibiting spleen-tyrosine-kinase lowers platelet/neutrophil NET formation and IL-1β/TNF-α surges linked to severe COVID-19, while indirectly easing micro-vascular thrombosis5,34,42,58,133 .
Possible treatments: fostamatinib, entospletinib, GS-9973, R406
300. LAIR-1 engagement & STAT1/JAK-STAT suppression
Engaging the inhibitory receptor LAIR-1 with polymerized type I collagen down-regulates STAT-1 phosphorylation, curbs JAK/STAT-driven cytokine output and thereby dampens COVID-19 hyper-inflammation120.
Possible treatments: collagen-PVP (polymerized type I collagen), LAIR-1-agonist peptides, collagen-mimetic hydrogels
301. IDO1 / kynurenine-pathway blockade
Viral IFN responses up-regulate IDO1, driving tryptophan catabolism and immunosuppression; selective IDO1 inhibitors cut kynurenine production and may restore antiviral T-cell function90,110.
Possible treatments: epacadostat, navoximod
302. Bruton's tyrosine-kinase (BTK) inhibition
BTK amplifies myeloid NF-κB / NLRP3 signaling; covalent BTK inhibitors curb IL-6 / IL-1β surges and improve survival in SARS-CoV-2-infected mice19,34,58 .
Possible treatments: ibrutinib, zanubrutinib, acalabrutinib, spebrutinib
303. Neurokinin-1 receptor (NK₁R) antagonism
Substance-P / NK₁R signaling drives pulmonary oedema and cytokine release; NK₁R antagonists restore fluid balance and damp inflammation in infected hamsters5,19.
Possible treatments: tradipitant, aprepitant, orvepitant
304. TLR4-spike protein interaction blockade
Spike protein directly binds TLR4 to enhance viral attachment, increase membrane surface virus concentration, and activate downstream inflammatory signaling, inducing antibacterial-like immune responses. Persistent TLR4 stimulation leads to NK cell exhaustion and long-COVID sequelae20,36,53,134 .
Possible treatments: paridiprubart (EB05), ApTOLL, eritoran (E5564), naltrexone, naloxone, tramadol, resatorvid (TAK-242), FP7, jacareubin, cajastelebenic acid, andrographolide, berberine, cannabidiol, disulfiram, dimethyl fumarate
305. NEU1/TLR-Siglec axis modulation
Inhibiting cell-surface NEU1 increases sialylation of innate-immune receptors, dampening TLR activation and cytokine surges; sialidase inhibition has rescued mice from infection-induced cytokine storm, suggesting a route to limit hyper-inflammation in COVID-1974.
Possible treatments: Neu5Ac2en-OAcOMe, other small-molecule NEU1 inhibitors
306. Mesenchymal stem cells (MSC)
MSCs possess potent immunomodulatory and regenerative properties, controlling cytokine storms by enhancing endogenous tissue repair and inhibiting immune system overactivation. They increase lymphocytes and regulatory DCs while lowering IL-6, CRP, IL-8, and TNF levels10.
Possible treatments: umbilical cord-derived MSCs, bone marrow-derived MSCs, adipose-derived MSCs, menstrual blood-derived MSCs
307. MSC-derived exosome therapy
Acellular therapeutic approach using MSC-derived exosomes that retain immune-modulatory, anti-inflammatory, and regenerative capabilities. They reduce cytokine storms, improve alveolar epithelium permeability, transport mitochondria to alveolar cells, and directly inhibit viral replication10.
Possible treatments: MSC-derived exosomes, engineered exosomes with specific miRNAs
308. Tollip C2-LC3 axis modulation to temper NF-κB and rebalance IFN signaling
Nsp14 binds Tollip (C2 domain), and Tollip over-expression or C2-containing fragments suppress Nsp14-mediated NF-κB activation. Tollip knockdown blunts IFNAR1/IFNGR1 loss during infection, implicating Tollip-guided lysosomal routing. Therapeutic concepts include boosting Tollip's NF-κB-restraining C2-LC3 function while selectively limiting receptor-degradative trafficking83.
Possible treatments: Tollip C2-domain peptides/mini-proteins, LC3-interaction enhancers, selective Tollip-trafficking modulators
309. AHR-driven Th17/Treg/Tr1 axis modulation
AHR skews CD4+ T-cell polarisation (Th17↑, Treg/Tr1 shifts) and dampens antiviral IFN signaling; phase-appropriate AHR modulation can rebalance immunity - antagonism earlier (proviral phase), cautious agonism in hyperinflammation57.
Possible treatments: CH-223191, GNF351, tapinarof, indole-3-carbinol, diindolylmethane
310. TonEBP preservation to sustain IFN-β transcription
3CLpro cleaves the transcription factor TonEBP, generating fragments that enhance viral replication and suppress IFN-β; preserving TonEBP function can support innate responses66.
Possible treatments: protease-resistant TonEBP fragments, small-molecule TonEBP activators
311. CSF1R (M-CSF receptor) inhibition
Predicted host factor CSF1R maps to marketed kinase inhibitors; dampening CSF1R signaling can reprogram inflammatory monocytes/macrophages and reduce lung inflammation in COVID-195,44,132 .
Possible treatments: imatinib
312. CX3CR1 (fractalkine) signaling modulation
Fractalkine-CX3CR1 drives neuron-microglia crosstalk and pro-inflammatory recruitment; down-modulation reduces microgliosis and cytokine output in neuroinflammation134.
Possible treatments: gabapentin, anti-CX3CR1 monoclonal antibodies, fractalkine-neutralizing biologics, small-molecule CX3CR1 antagonists
313. Acetylcholinesterase inhibition
Inhibition of acetylcholinesterase to increase acetylcholine levels, which can modulate the cholinergic anti-inflammatory pathway, potentially reducing cytokine storm and improving respiratory muscle function5.
Possible treatments: pyridostigmine bromide
314. Alpha-2 adrenergic receptor agonism
Activation of alpha-2 adrenergic receptors, which can produce sedative and anti-inflammatory effects, potentially mitigating hyperinflammation in severe COVID-195.
Possible treatments: dexmedetomidine
315. Macrolide immunomodulation
Utilizing macrolide antibiotics for their secondary immunomodulatory properties, which can dampen excessive inflammatory responses5.
Possible treatments: azithromycin, fidaxomicin
316. Beta-adrenergic blockade
Modulation of the adrenergic system to produce anti-inflammatory effects and potentially alter ACE2 expression or function, thereby reducing the host inflammatory response to infection5.
Possible treatments: timolol maleate
317. TonEBP (NFAT5) preservation to sustain IFN-β transcription
The viral main protease (3CLpro/Mpro) cleaves the transcription factor TonEBP. The resulting N-terminal fragment translocates to the nucleus and competitively inhibits p65 binding on the IFN-β promoter, suppressing the interferon response. Protecting TonEBP from cleavage may help maintain innate immune signaling68.
Possible treatments: protease-resistant TonEBP-derived peptides, small-molecule TonEBP activators
318. ATF3 modulation for immune homeostasis
Modulating the transcription factor ATF3 to restore immune balance. ATF3 is a stress-responsive transcription factor that enhances STAT1-ISG antiviral programs and reduces NF-κB/TNF-α/IL-6 overexpression58.
Possible treatments: integrated-stress-response activators (e.g., 4-octyl-itaconate/itaconate esters), naringin, ATF3-inducing small molecules
319. STAT3 pathway inhibition (anti-inflammatory / anti-fibrotic axis)
Hyperactivated STAT3 amplifies IL-6 signaling, promotes fibrosis, and sustains cytokine storm; dampening STAT3 (or upstream JAKs) reduces inflammatory drive and ACE2 upregulation58,135,136 .
Possible treatments: baricitinib, ruxolitinib, 6-O-angeloylplenolin (phospho-STAT3 inhibitor candidates), , KVX-053
320. SGK3-tuned STING/IRF7 axis modulation
DNA/RNA-sensing (cGAS-STING) and IRF3/7 responses are partly SGK-kinase-dependent; SGK3 inhibition can recalibrate STING-IRF signaling to restore antiviral balance without overshooting inflammation58.
Possible treatments: AGC-kinase/SGK3 inhibitors
321. CD44-mediated neutrophil infiltration inhibition
Blocking CD44, the primary receptor for hyaluronan (HA), reduces neutrophil infiltration into the lungs, thereby preventing excessive inflammatory responses and lung tissue damage in COVID-19122.
Possible treatments: KM201, IM7
322. Hyaluronan-mediated immune cell retention
HA deposition in the lungs interacts with CD44, promoting neutrophil retention and exacerbating inflammation. Targeting HA-CD44 interactions may prevent the formation of a pathogenic HA matrix and reduce lung damage122.
Possible treatments: hyaluronidase, HA-binding domain inhibitors
323. PIGR/secretory IgA transport enhancement
PIGR mediates transcytosis of dimeric IgA/M to mucosa; strong diagnostic performance motivates strategies that boost PIGR or deliver sIgA to reinforce mucosal neutralization at the airway entry portal4,91.
Possible treatments: recombinant dimeric IgA (sIgA), PIGR expression agonists (experimental), Cv2.1169, MAb362, ZW2G10, H4, B38, SA55 IgA1, S2-3-IgA2m2
324. SERPINA5 (Protein C inhibitor) normalization for barrier + antiviral signaling
Downregulated in COVID-19; SERPINA5 regulates serine-protease activity and supports STAT1 phosphorylation/nuclear translocation. Normalizing levels may curb protease-driven tissue damage and improve antiviral responses137.
Possible treatments: SERPINA5 replacement/induction (research-stage), STAT1-pathway supportive agents
325. HSPA8 inhibition
Inhibition of HSPA8, a key hub protein involved in protein homeostasis and immune response regulation. Dysregulation of HSPA8 in COVID-19 patients contributes to immune dysregulation and viral pathogenesis34.
Possible treatments: MKT-077, HSPA8 inhibitors
326. HSPA9 inhibition
Inhibition of HSPA9, a protein involved in immune regulation and cell stress responses. HSPA9 is implicated in the regulation of apoptotic pathways and immune modulation during SARS-CoV-2 infection. Targeting HSPA9 could help restore immune homeostasis and reduce viral persistence34.
Possible treatments: MKT-077, HSPA9 inhibitors
327. SRC inhibition
Inhibition of SRC, a protein involved in immune response regulation, inflammation, and coagulation. SRC plays a central role in immune dysregulation in COVID-1934.
Possible treatments: dasatinib, bosutinib
328. STAT1 restoration
Restoring STAT1 activity to enhance immune responses and inhibit viral replication. Despite transcriptional upregulation, STAT1 is often downregulated in COVID-19, suggesting viral interference in interferon responses34.
Possible treatments: AVT-02 (acitretin), JAK inhibitors
329. TNF-α decoy receptors
Soluble decoy receptors, such as the extracellular domain of TNFR2, that bind to and neutralize tumor necrosis factor (TNF-α). This blocks pro-inflammatory signaling pathways, helping to mitigate the cytokine storm associated with severe COVID-1929,132.
Possible treatments: etanercept, ACE2(M)-Fc-TNFR2, Fc-TNFR2
330. IL-6 trans-signaling inhibition (GP130 decoy)
Soluble forms of the GP130 receptor that specifically bind the IL-6/IL-6R complex. This selectively blocks the pro-inflammatory IL-6 trans-signaling pathway while sparing the anti-inflammatory classical signaling, offering a more targeted approach to dampening IL-6-mediated cytokine storm16,29.
Possible treatments: Olamkicept (sGP130-Fc), ACE2(M)-Fc-GP130, ferulic acid, kaempferol, quercetin, tryptanthrin, quinapril
331. PARP14 antiviral ADP-ribosylation preservation
PARP14 is an interferon-stimulated mono-ADP-ribosyltransferase that modifies host and viral proteins to inhibit replication. SARS-CoV-2 Mac1 reverses this activity to evade immunity, preserving PARP14-mediated MARylation enhances viral clearance79.
Possible treatments: Mac1 inhibitors (indirect preservation)
332. BCL2 restoration for lymphocyte survival
SARS-CoV-2 infection (via CD147 entry) downregulates BCL2 and upregulates BAX/BAK1, driving apoptosis in CD4+ T cells and B cells. Restoring BCL2 levels or blocking CD147 reverses this lymphopenia and restores adaptive immune competence15,138.
Possible treatments: Jinhong decoction, dandelion flavonoids, meplazumab
333. TLR1 antagonism (E protein mediated)
The SARS-CoV-2 Envelope (E) protein binds and activates Toll-like Receptor 1 (TLR1) on myeloid cells, inducing robust pro-inflammatory cytokine production independent of viral entry. Note that M protein binds but does not activate TLR135.
Possible treatments: TLR1 antagonists
334. GFPT2/hexosamine biosynthesis pathway (HBP) enhancement
GFPT2, the rate-limiting enzyme of the hexosamine biosynthesis pathway, interacts with MAVS at mitochondria-associated membranes (MAMs) to couple metabolic status with sustained type-I IFN responses. Enhancing GFPT2 activity can boost MAVS-mediated antiviral immunity22.
Possible treatments: GFPT2 activators, O-GlcNAc enhancers, glucosamine
335. JAK2 signaling inhibition
JAK2 acts as an intermediary in cytokine regulation and STAT phosphorylation; JAK2 deficiency reduces neutrophil infiltration and pro-inflammatory cytokine expression in ARDS23.
Possible treatments: apigenin-7-glucoside, quercetin, pistagremic acid, linolenic acid
336. Type I interferon-stimulated gene (ISG) hub modulation
Targeting hub genes (OAS2, MX1, IRF7, RSAD2, OASL, IFIT1, IFIT3, ISG15) that are upregulated. These genes show strong diagnostic performance (AUC>0.7 for COVID-19) and correlate with neutrophil and Th17 cell infiltration40,85.
Possible treatments: JAK inhibitors, type I IFN modulators, ISG-targeted therapies
337. OAS/OASL (2'-5'-oligoadenylate synthetase) pathway modulation
The OAS family genes (OAS1, OAS2, OAS3, OASL) are key ISGs that activate RNase L to degrade viral RNA. Dysregulated OAS activity contributes to both antiviral defense and autoimmune pathology40,85,98 .
Possible treatments: RNase L modulators, OAS pathway inhibitors
338. MX protein (MX1/MX2) dynamin-like GTPase modulation
MX1 is a hub ISG with strong antiviral activity against multiple RNA viruses including SARS-CoV-2. Elevated in COVID-19 nasopharyngeal epithelium, MX1 upregulation correlates with disease severity and immune cell infiltration85,98.
Possible treatments: IFN-β (indirect), MX1 modulators
339. IRF7 (Interferon Regulatory Factor 7) modulation
IRF7 is a master transcriptional regulator of type I interferon responses and a validated hub gene in COVID-19. IRF7 upregulation drives ISG expression cascades; its dysregulation contributes to both inadequate early antiviral responses and later immunopathology85.
Possible treatments: IRF7 modulators, upstream kinase inhibitors
340. RSAD2 (Viperin) antiviral effector modulation
RSAD2/Viperin is an ISG that inhibits viral replication by disrupting lipid rafts and viral budding. Identified as a hub gene upregulated in COVID-19 epithelial cells, RSAD2 represents both an antiviral defense mechanism and a marker of interferon pathway activation31,85.
Possible treatments: IFN pathway modulators
341. IFIT family (IFIT1/IFIT3) translation inhibitor modulation
IFIT1 and IFIT3 are ISGs that inhibit viral protein translation by binding viral RNA lacking 2'-O-methylation. Both are hub genes showing high diagnostic accuracy. Their expression correlates with neutrophil and Th17 infiltration85.
Possible treatments: IFN modulators, translation regulation therapies
342. Lysine demethylase 1 (LSD1/KDM1A) inhibition
LSD1 inhibitors specifically suppress inflammation while preserving IFN-mediated antiviral activity. DDP38003 blocked viral release via the lysosomal acidification pathway and enhanced IFN-independent antiviral mechanisms, balancing inflammation control with antiviral effects in K18-hACE2 mice26.
Possible treatments: DDP38003, iadademstat, tranylcypromine, ORY-1001
343. Galectin-9 (Gal-9) immunomodulatory therapy
Circulating galectin-9 has immunomodulatory properties and binds specifically to the host ACE2 receptor. Recombinant humanized gal-9 significantly alleviated acute-phase lethal infection in K18-hACE2 mice26.
Possible treatments: recombinant humanized galectin-9
344. Pulmonary surfactant-mediated TLR4 suppression
Alveolar Type II (ATII) cells produce surfactant lipids, specifically palmitoyl-oleoyl-phosphatidylglycerol (POPG), which normally antagonize TLR4. SARS-CoV-2 induces ATII apoptosis, depleting POPG and releasing the brake on TLR4-driven hyperinflammation. Surfactant replacement restores this inhibition40,53,71 .
Possible treatments: Lung Surfactant-BL, calfactant, poractant alfa, POPG
345. PTP4A3 (PRL-3) phosphatase inhibition
PTP4A3 is a dual-specificity phosphatase upregulated in the lungs during lethal COVID-19. It acts as a critical upstream regulator of the inflammatory response by modulating STAT3 phosphorylation, NF-κB activation, and NLRP3 inflammasome assembly. Inhibition mitigates cytokine storm, reduces macrophage infiltration, and preserves lung parenchymal integrity135.
Possible treatments: KVX-053 (JMS-053), PRL3-zumab
346. Fc domain engineering (Afucosylation/Mutations)
Modulating antibody Fc domains to enhance effector functions (ADCC/ADCP). Afucosylation increases FcγRIIIa affinity, while specific mutations boost Fc receptor binding to improve clearance of infected cells2,4,139 .
Possible treatments: afucosylated antibodies, GASDALIE variants, GAALIE variants, S239D/I332E mutants, CV3-13, DH1052, COVA2-18, AZD8895, AZD1061
347. FGFR1 signaling inhibition
Fibroblast Growth Factor Receptor 1 (FGFR1) signaling activates the downstream MEK/ERK pathway to suppress the host innate immune response (type I interferon). Inhibiting FGFR1 relieves this suppression, enhancing the expression of IFN-β and interferon-stimulated genes to restrict viral replication61.
Possible treatments: infigratinib (BGJ398), pemigatinib, erdafitinib
348. CD59 (Protectin) blockade
CD59 is a lipid-raft associated GPI-anchored protein upregulated by viral structural proteins. It inhibits the complement membrane attack complex (MAC). The virus may exploit CD59 to prevent complement-mediated lysis of infected cells; blocking may enhance immune clearance39.
Possible treatments: recombinant intermedilysin (ILY), blocking antibodies
349. ZBP1 (Z-DNA Binding Protein 1) modulation
ZBP1 is a robustly upregulated innate immune sensor that detects viral Z-RNA, and drives inflammatory cell death (PANoptosis) and lung inflammation. Modulating ZBP1 sensing can influence viral clearance and the severity of immunopathology116.
Possible treatments: necroptosis inhibitors (indirect)
350. TGF-β signaling inhibition
Transforming Growth Factor Beta 1 (TGFB1) and its receptor (TGFBR2) are identified as central hub genes in the heart and lung transcriptomes of infected patients. They drive pathological fibrosis, immune suppression, and epithelial-mesenchymal transition55.
Possible treatments: irinotecan, inositol, pirfenidone, galunisertib, vactosertib, fresolimumab
351. M2 Macrophage communication restoration
SARS-CoV-2 infection disrupts cell-cell communication networks, specifically inducing abnormal interactions between M2 macrophages and AT2/CD8+ T cells that drive immunosuppression. Blocking the CD147-Spike axis restores homeostatic macrophage communication15.
Possible treatments: meplazumab
352. CD47/SIRPα checkpoint blockade
Inhibiting the interaction between CD47 and SIRPα on blood and immune cells. Blockade enhances the phagocytosis of infected cells and RBCs, potentially reducing thrombosis and stroke risk16.
Possible treatments: L-asparaginase, amygdalin, phytic acid, quercetin, kaempferol, apigenin, quinapril, molsidomine
353. MIF (Macrophage Migration Inhibitory Factor) antagonism
MIF is robustly secreted by SARS-CoV-2 infected neuron-astrocyte co-cultures. It promotes broad inflammatory responses and immune cell recruitment, contributing to cytokine storm and severity33.
Possible treatments: ibudilast, ISO-1, goxalapladib
354. Lysosomal/Autophagic modulation for B-cell preservation
SARS-CoV-2 Spike protein, particularly in the presence of environmental endocrine disruptors (e.g., Bisphenol A), triggers excessive autophagic flux and lysosomal intracellular activity leading to B-cell death. Inhibiting this hyperactivation preserves B-cell viability and humoral immune function140.
Possible treatments: ursodeoxycholic acid
355. IL-7 mediated lymphocyte reconstitution
Recombinant human IL-7 (rhIL-7) reverses severe lymphopenia and improves T-cell function (CD4+/CD8+) in critically ill or immunosuppressed patients. Unlike generalized immunostimulants, IL-7 restores protective adaptive immunity without precipitating cytokine storms123.
Possible treatments: CYT107 (efineptakin alfa), recombinant human IL-7
356. IL-22 mediated epithelial repair & viral entry suppression
IL-22 signaling via the IL-22R1/IL-10R2 complex promotes epithelial regeneration, barrier protection, and anti-apoptotic effects in lung tissue. Additionally, IL-22 downregulates SARS-CoV-2 entry receptors (ACE2 and TMPRSS2) while enhancing antiviral protein expression123.
Possible treatments: recombinant IL-22, IL-22-Fc fusion proteins
357. IL-33/ST2 axis blockade
IL-33 acts as an alarmin released from damaged alveolar epithelium, driving type-2 immune responses, neutrophil infiltration, and thrombosis via the ST2 signaling pathway. High levels inhibit antiviral immunity and predict adverse outcomes123.
Possible treatments: anti-ST2 antibodies, anti-IL-33 antibodies, etokimab, itepekimab, astegolimab
358. IL-36 pathway inhibition
IL-36 (IL-1 superfamily) promotes a pro-inflammatory feedback loop driving IL-6 and IL-8 production. It is implicated in endothelial injury and potential cutaneous/intestinal manifestations of COVID-19 via crosstalk with the ACE2-angiotensin axis123.
Possible treatments: spesolimab, imsidolimab, IL-36 receptor inhibitors
359. LILRB3 (ILT5/CD85a) immune checkpoint blockade
Inhibition of the LILRB3 inhibitory receptor on myeloid cells. Severe COVID-19 patients exhibit early upregulation of LILRB3, which is hypothesized to suppress Fc-effector functions of classical monocytes. Blocking this checkpoint may restore efficient antibody-opsonized viral clearance and temper hyperinflammation139.
Possible treatments: LILRB3 antagonists, anti-LILRB3 monoclonal antibodies
360. ETS1 transcription factor inhibition
ETS1 is a key driver of the severity-associated IL7R+ classical monocyte subtype, which adopts T cell-like signaling features. ETS1 activation induces a hypo-inflammatory phenotype, Wnt signaling, and TGF-β secretion. While this may blunt acute hyperinflammation, it also suppresses antiviral functions and drives profibrotic processes. Inhibiting ETS1 shifts monocytes back toward an antiviral M1-like state141.
Possible treatments: ETS1 inhibitors
361. JDP2 (Jun Dimerization Protein 2) inhibition
JDP2 acts as a transcriptional repressor of the AP-1 family in CD163+ classical monocytes, maintaining an M2-like anti-inflammatory and profibrotic identity. Inhibiting JDP2 restores AP-1 transcriptional activity, upregulates pro-inflammatory and antiviral genes, and shifts monocytes toward an M1-like state, potentially preventing excessive fibrosis and immunosuppression during severe COVID-19141.
Possible treatments: JDP2 inhibitors
362. CCL2/CCR2 axis blockade
Targeting the CCL2-CCR2 axis limits pathological monocyte recruitment into the respiratory system, reducing cytokine storms, myeloid cell accumulation, and extensive alveolar injury136,142.
Possible treatments: cenicriviroc, CCR2 inhibitors, CCR2/CCR5 dual antagonists
363. Spike-IL-6R direct interaction blockade
The Spike protein demonstrates high binding affinity for the interleukin-6 receptor (IL-6R). This direct receptor interaction suggests IL-6R plays an important role in perpetuating the inflammatory state and endothelial dysfunction observed in SARS-CoV-2 infection, potentially acting as an alternative viral receptor36.
Possible treatments: IL-6R antagonists, tocilizumab, sarilumab
364. TLR2 and TLR7-Spike interaction blockade
In addition to TLR4, the SARS-CoV-2 Spike protein shows high binding affinity for Toll-like receptors 2 and 7 (TLR2, TLR7). These receptors can serve as alternative pathways for establishing an inflammatory phenotype in the endothelium36.
Possible treatments: TLR2 antagonists, TLR7 antagonists
365. CXCL13/CXCR5 chemokine axis stimulation
Stimulating the CXCL13/CXCR5 chemokine axis promotes the recruitment and maintenance of protective antiviral CXCR5+ B cells, follicular helper T cells (Tfh), and effector Th1 cells in the lungs143.
Possible treatments: recombinant CXCL13, CXCR5 agonists
366. NMDAR (N-methyl-d-aspartate receptor) antagonism
NMDAR antagonists offer neuroprotective properties against excitotoxicity and can inhibit the onset of severe neuro-inflammatory responses and microglial activation linked to cognitive decline132.
Possible treatments: memantine, ifenprodil
367. Extracellular Vesicle (EV)-mediated Vδ2 T-cell hyperactivation blockade
Circulating extracellular vesicles (EVs) from severe COVID-19 patients deliver molecular signals that enhance the responsiveness of innate Vδ2 T cells to phosphoantigens, resulting in increased production of pro-inflammatory cytokines like TNF-α, exacerbating immune-driven inflammation. Targeting EV-mediated intercellular communication could mitigate this axis of immunopathology125.
Possible treatments: EV uptake inhibitors, TNF-α inhibitors
368. PAD4-mediated citrullination blockade
Inhibition of PAD4 reduces the infection-induced hyper-citrullination of host proteins and suppresses pro-inflammatory cytokine expression, thereby mitigating virus-induced hyperinflammation and immune dysregulation93.
Possible treatments: GSK199, GSK484, BB-Cl-amidine, Cl-amidine
369. PAD2 (Peptidyl-arginine deiminase 2) preservation
SARS-CoV-2 infection induces a dramatic reduction of PAD2 expression in the brain. Since PAD2 is essential for synaptic function and chronic inflammation control in the central nervous system, its downregulation may exacerbate neuroinflammation. Preserving PAD2 activity could mitigate neurological sequelae93.
Possible treatments: PAD2 agonists
370. HCN3 (hyperpolarization-activated cyclic nucleotide-gated channel 3) modulation
Multi-trait conditional analysis identifies HCN3 as a COVID-19-specific risk gene. Lower genetically predicted expression of HCN3 in lung and whole blood is associated with increased risk of severe COVID-1940.
Possible treatments: HCN channel modulators, ivabradine, ZD7288
371. ATP11A phospholipid flippase modulation
Multi-omics shared-signal analysis identifies ATP11A as exhibiting strong discordant pleiotropic effects between COVID-19 and idiopathic pulmonary fibrosis (IPF): increased expression in blood is associated with higher IPF risk but is protective against severe COVID-19. Validated across MAGMA, TWAS, and spTWAS40.
Possible treatments: ATP11A modulators
372. CSF2RB/GM-CSF-driven surfactant metabolism dysfunction
Genome-wide differential pathway analysis identifies defective CSF2RB (causing pulmonary surfactant metabolism dysfunction type 5) as a COVID-19-specific pathway. CSF2RB encodes the GM-CSF receptor beta chain, critical for alveolar macrophage maturation and surfactant clearance. Genetic predisposition to severe COVID-19 involves a distinct failure in the GM-CSF/alveolar macrophage axis leading to surfactant dysregulation and cellular debris accumulation, characteristic of ARDS40.
Possible treatments: sargramostim (inhaled rh-GM-CSF), mavrilimumab, lenzilumab, otilimab
373. PCSK9 inhibition
Blocking PCSK9-mediated LDL receptor degradation indirectly reduces viral attachment to host cells and dampens cytokine storm17.
Possible treatments: evolocumab, lerodalcibep
374. S1P1 and S1P5 receptor activation
Activation of sphingosine-1-phosphate (S1P) signaling restrains cytokine storm, reduces lung pathology, and improves survival in preclinical models of viral infection17.
Possible treatments: ozanimod
375. Prostaglandin D2 receptor 1 (DP1) inhibition
Inhibition of DP1 signaling enhances the adaptive immune response to viral infection in preclinical models17.
Possible treatments: BGE-175
376. 25-Hydroxycholesterol (25-HC) ISG amplification
The cholesterol metabolite 25-hydroxycholesterol (25-HC), produced by the interferon-inducible enzyme CH25H, exerts broad antiviral activity through dual mechanisms: direct inhibition of membrane fusion of enveloped viruses including SARS-CoV-2, and amplification of interferon-stimulated gene (ISG) expression through modulating the activity of the cholesterol biosynthetic sensor INSIG. Boosting 25-HC production represents a host-directed strategy linking lipid metabolism to innate antiviral immunity17.
Possible treatments: 25-hydroxycholesterol, CH25H inducers, oxysterol analogs
377. Notch4 receptor inhibition on Regulatory T (Treg) cells
Targeting Notch4 expression on peripheral circulating Treg cells. High Notch4 expression emerges as a late marker of mortality in severe COVID-19, correlating with decreased regulatory capacity, a shift toward a proinflammatory profile, hypoxia, and multiple organ failure. Inhibiting Notch4 may restore Treg function and immune homeostasis in critically ill patients129.
Possible treatments: Notch4 inhibitors, anti-Notch4 monoclonal antibodies
Microbiome Modulation
Mechanisms that modulate the microbiome to enhance antiviral activity or reduce immunopathology.
378. Upper-respiratory probiotic / synbiotic therapy
Re-establish eubiotic taxa (e.g. Dolosigranulum sp., Lachnospiraceae, Propionibacteriaceae) to enhance local SCFA and vitamin B12/K output, reinforce mucin glycosylation and prime MAIT-cell / dendritic-cell antiviral responses57,128.
Possible treatments: Intranasal Lactobacillus casei spray, Streptococcus salivarius K12 lozenges, Dolosigranulum pigrum lysate drops
379. Probiotic TLR4/NLRP3 modulation
Specific probiotic strains (e.g., Lactobacillus paracasei F19) produce bioactive lipids (like palmitoylethanolamide) or peptides that block TLR4 signaling and downstream NLRP3 inflammasome activation, reducing lung injury and cytokine release53.
Possible treatments: Lactobacillus paracasei F19, Bacillus-fermented soybean peptide
Hemostasis & Thrombosis Management
Mechanisms that address coagulopathy and prevent thrombosis, common in severe COVID-19.
380. Anticoagulant therapy
Possible treatments: heparin, enoxaparin, dalteparin, tinzaparin
381. Antiplatelet therapy
Possible treatments: aspirin, clopidogrel, caplacizumab
382. Direct thrombin inhibitors
Inhibit thrombin activity to prevent fibrin formation137.
Possible treatments: dabigatran, argatroban, bivalirudin, lepirudin
383. Direct factor Xa inhibitors
Directly inhibit factor Xa to reduce thrombin generation.
Possible treatments: rivaroxaban, apixaban, edoxaban
384. Indirect factor Xa inhibitors
Enhance antithrombin-mediated inhibition of factor Xa.
Possible treatments: fondaparinux
385. Vitamin K antagonists
Inhibit synthesis of vitamin K-dependent clotting factors.
Possible treatments: warfarin
386. P2Y12 receptor inhibitors
Block ADP-induced platelet activation and aggregation.
Possible treatments: clopidogrel, prasugrel, ticagrelor, ticlopidine
387. Glycoprotein IIb/IIIa inhibitors
Prevent fibrinogen binding and platelet cross-linking16.
Possible treatments: abciximab, eptifibatide, tirofiban, L-asparaginase, quercetin, apigenin, phytic acid
388. Phosphodiesterase inhibitors
Increase cAMP levels, reducing platelet activation.
Possible treatments: dipyridamole, cilostazol
389. Protease-activated receptor-1 antagonists
Inhibit thrombin-induced platelet aggregation.
Possible treatments: vorapaxar
390. Fibrinolytic agents
Lyse existing thrombi by converting plasminogen to plasmin137.
Possible treatments: alteplase, tenecteplase, reteplase, streptokinase
391. Antithrombin III supplementation
Supplement antithrombin to enhance anticoagulation.
Possible treatments: antithrombin III concentrate
392. Heparin-like agents
Exert anticoagulant effects similar to heparin.
Possible treatments: danaparoid
393. NSP3-fibrinogen interaction blockade
Agents that obstruct extracellular NSP3 binding to fibrinogen, normalizing fibrin formation and mitigating virus-driven hyper-coagulation144,145.
Possible treatments: anti-fibrinogen-site peptides, NSP3 protease inhibitors
394. Platelet FcγRIIa blockade
Monoclonal antibodies or engineered Fc fragments that block IgG engagement of platelet FcγRIIa, preventing afucosylated IgG-driven platelet activation and thrombus formation133.
Possible treatments: anti-FcγRIIa mAb (IV.10), FcγRIIa-Fc chimera, Syk-decoy peptides
395. Serotonin transporter / 5-HT receptor inhibition
SSRIs decrease intraplatelet serotonin; 5-HT₂/5-HT₃ antagonists blunt serotonin-amplified aggregation, collectively reducing COVID-19-associated thrombosis5,133.
Possible treatments: fluvoxamine, sertraline, fluoxetine, vortioxetine, ketanserin, granisetron
396. ORF7a-triggered endothelial VWF release blockade
SARS-CoV-2 ORF7a activates Weibel-Palade body exocytosis, unleashing ultralarge VWF multimers that enhance platelet adhesion and accelerate thrombus formation. Therapeutic focus: restore ADAMTS-13/VWF balance or block VWF-platelet binding47,137,144,146 .
Possible treatments: recombinant ADAMTS-13, caplacizumab, VWF-neutralizing antibodies
397. Tissue Factor Pathway Inhibitor (TFPI) augmentation (extrinsic-pathway brake)
Boost the endogenous inhibitor of the TF-FVIIa complex to damp extrinsic coagulation drive implicated in COVID-19 CCC dysregulation137.
Possible treatments: recombinant TFPI (tifacogin-class), TFPI-mimetics
398. Thrombomodulin (THBD) activation / recombinant thrombomodulin
Enhance the thrombin-thrombomodulin-protein C axis to neutralize prothrombotic signaling while preserving anticoagulant and anti-inflammatory effects137.
Possible treatments: recombinant thrombomodulin (ART-123/thrombomodulin alfa)
399. Protein C pathway restoration (PROC/SERPINC1 axis)
Restore impaired natural anticoagulant circuits noted among CCC hubs (PROC, SERPINC1), aiming to reduce microthrombi and immunothrombosis137.
Possible treatments: protein C concentrate, antithrombin concentrate
400. Fibrinogen β/γ (FGB/FGG)-driven fibrin deposition moderation
Upregulated FGB/FGG associate with excessive fibrin formation and possible profibrotic TGF-β crosstalk; moderating polymerization may reduce microvascular obstruction and downstream fibrosis137.
Possible treatments: GPRP-analogue fibrin-polymerization blockers, adjunct antifibrotics
401. Prothrombin (F2) level/function normalization
Meta-analysis shows F2 downregulation; careful, context-specific normalization may restore hemostatic balance while avoiding prothrombotic overshoot137.
Possible treatments: prothrombin complex concentrates
402. α2-Antiplasmin (SERPINF2) tuning
As a CCC hub, SERPINF2 (plasmin inhibitor) modulation could re-balance fibrinolysis vs. thrombosis in COVID-associated coagulopathy125,137.
Possible treatments: plasmin/α2-antiplasmin interface modulators
403. CD36-mediated platelet activation (E protein)
The membrane protein CD36 acts as a specific receptor for the SARS-CoV-2 Envelope (E) protein on platelets. This interaction triggers p38 MAPK and NF-κB signaling, leading to platelet activation and thrombosis35.
Possible treatments: CD36 inhibitors
404. Platelet TLR4 signaling inhibition
Spike protein activates platelets via TLR4 (and ACE2/TMPRSS2), triggering granule release, thrombin generation, and NET formation. Thrombin creates a feedback loop by enhancing TLR4 surface expression on platelets via PAR1/PAR4-mediated calcium mobilization and calpain activation53.
Possible treatments: tramadol, thrombin inhibitors, TLR4 antagonists
405. Serpin E1 (PAI-1) inhibition
Serpin E1 (Plasminogen Activator Inhibitor-1) is significantly upregulated in infected neuron-astrocyte cultures. It inhibits fibrinolysis (promoting coagulopathy) and suppresses microglial phagocytosis, potentially exacerbating neuroinflammation33,36.
Possible treatments: tiplaxtinin, TM5275, MDI-2517
406. Kynurenine-AHR-TF axis / IDO-1 blockade
SARS-CoV-2 infection upregulates enzymes regulating kynurenine biogenesis and suppresses catabolic enzymes. The resulting elevated kynurenine activates the aryl hydrocarbon receptor (AHR) signaling pathway, which upregulates tissue factor (TF) on endothelial cells and drives microvascular thrombosis. Co-inhibition of IDO-1 and AHR synergistically suppresses TF-induced procoagulant activity110.
Possible treatments: CH223191, INCB024360
407. Spike-Thrombomodulin (CD141) interaction blockade
SARS-CoV-2 Spike protein has a high affinity for endothelial thrombomodulin (CD-141). This direct interaction may inhibit the thrombomodulin-thrombin-activated protein C pathway, contributing to the endothelial dysfunction and active immunothrombotic process observed in COVID-1936.
Possible treatments: thrombomodulin decoys, Spike-THBD interface disruptors
408. IL-1β / IL-1R signaling blockade (Endothelial Protection)
Blocking IL-1 signaling to prevent epithelial-derived IL-1β from driving downstream TNF production and subsequent endothelial dysfunction. IL-1β inhibition maintains VE-cadherin junctional integrity, prevents endothelial cell death, and significantly mitigates fibrin deposition and platelet adherence124.
Possible treatments: anakinra, canakinumab, anti-IL-1β antibodies
409. TNF signaling blockade (Endothelial Protection)
Neutralizing epithelial-derived tumor necrosis factor (TNF) prevents it from acting on adjacent endothelial cells. Specific TNF blockade inhibits endothelial ICAM-1 expression, preserves VE-cadherin junctions, and blocks endothelial cell death124.
Possible treatments: adalimumab, infliximab, anti-TNF antibodies
410. Platelet-derived Extracellular Vesicle (EV) modulation
Severe COVID-19 is associated with a significantly higher frequency of platelet-derived EVs compared to mild cases or healthy donors. The proteomic cargo of these EVs is highly enriched for proteins involved in platelet degranulation and coagulation cascades. Modulating the release or activity of these EVs may help manage virus-associated coagulopathy125.
Possible treatments: antiplatelet agents, EV release inhibitors
411. PAD4-dependent NETosis inhibition
PAD4 catalyzes the citrullination of histones, a critical step for the release of neutrophil extracellular traps (NETs). Excessive NET formation drives immunothrombosis and lung injury in severe COVID-19. PAD4 inhibitors reduce NET accumulation and improve outcomes93.
Possible treatments: GSK199, GSK484, BB-Cl-amidine, Cl-amidine
412. Prostacyclin analogs
Promotes vasodilation in the pulmonary vasculature, which improves inflammation and oxygenation in COVID-19 patients experiencing ARDS17.
Possible treatments: epoprostenol, iloprost
Inflammation & Oxidative Stress Reduction
Mechanisms that reduce tissue damage caused by inflammation and oxidative stress.
413. Nrf2 activation
Enhancing host antioxidant, anti-inflammatory and antiviral defences by activating transcription-factor Nrf2. Upregulates phase-II enzymes (HO-1, NQO1, TRXR), suppresses NF-κB, tempers STING-driven IFN-I output, and downregulates entry factors ACE2/TMPRSS217,50,52,58,140 .
Possible treatments: sulforaphane, bardoxolone methyl, dimethyl fumarate, resveratrol, curcumin, oltipraz, PB125, epigallocatechin gallate, ursodeoxycholic acid
414. Matrix metalloproteinase (MMP) inhibition
Reducing inflammation and vascular leakage. Excess MMP-9 promotes lung barrier breakdown and cytokine storm; selective or broad-spectrum MMP inhibitors blunt this damage94,138,142 .
Possible treatments: doxycycline, minocycline, marimastat, batimastat, quercetin, EGCG, SB-3CT, Jinhong decoction, rhubarbic acid
415. COX-2 inhibition
Possible treatments: celecoxib, etoricoxib, meloxicam, boswellic acids, curcumin, GPR4 antagonists, NE-52-QQ57
416. NF-κB / RELA (p65) inhibition
Inhibition of pro-inflammatory transcription factor NF-κB (specifically the RELA/p65 subunit) to reduce cytokine production and viral replication23,58,91,116,134,135,146,147 .
Possible treatments: parthenolide, curcumin, quercetin, celastrol, sulforaphane, apigenin-7-glucoside, swertanone, pistagremic acid, KVX-053
417. ROS scavenging
Neutralizing reactive oxygen species to prevent oxidative damage.
Possible treatments: vitamin C, vitamin E, melatonin, CoQ10, N-acetylcysteine, alpha-lipoic acid
418. Glutathione enhancement
Boosting endogenous glutathione synthesis or regeneration26.
Possible treatments: N-acetylcysteine, alpha-lipoic acid, glutathione, sulforaphane
419. NLRP1/NLRP10 inflammasome inhibition
Selective blockade of caspase-1 activation downstream of NLRP1/10 mitigates IL-1β release and pyroptotic damage in infected airway cells, complementing NLRP3-directed approaches66,68.
Possible treatments: VX-765, belnacasan (VX-740)
420. NLRP3 inflammasome inhibition
Possible treatments: MCC950, glyburide, resveratrol, parthenolide, quercetin, luteolin, Harrisonia perforata, KVX-053
421. SOD mimetics
Mimicking superoxide dismutase to neutralize superoxide radicals.
Possible treatments: tempol, MnTBAP
422. Heme oxygenase-1 (HO-1) induction
Inducing the Nrf2-dependent enzyme HO-1 yields CO, biliverdin and bilirubin, providing antioxidant, cytoprotective and broad antiviral effects that limit viral replication and lung injury50,51,58 .
Possible treatments: hemin, cobalt protoporphyrin, sulforaphane, dimethyl fumarate, resveratrol, curcumin
423. SIRT1 activation
SIRT1 deacetylates the NF-κB p65 subunit to suppress cytokine storms (IL-6, TNF-α), stabilizes Nrf2 to combat oxidative stress, and regulates ACE2 expression. In the acute phase, SIRT1 activation dampens hyperinflammation and endothelial dysfunction, while in recovery it promotes mitochondrial homeostasis and tissue repair149.
Possible treatments: resveratrol, quercetin, curcumin, hesperetin, berberine, fisetin, silibinin, luteolin, NAD+ precursors, nicotinamide riboside, metformin
424. PPAR-γ activation
Possible treatments: pioglitazone, rosiglitazone, curcumin
425. Ferroptosis inhibition
Blocking iron-dependent lipid peroxidation cell death pathways activated during SARS-CoV-2 infection, which may contribute to tissue damage particularly in the lungs. This approach targets the GPX4/GSH antioxidant system, iron metabolism regulation, and lipid peroxidation processes52,62,150 .
Possible treatments: ferrostatin-1, liproxstatin-1, deferoxamine, N-acetylcysteine, vitamin E, ebselen, baicalein, pyrvinium, pyridoxal 5'-phosphate, famotidine, astemizol
426. Vinculin/ICAM-1 pathway modulation
Targeting the host cytoskeletal adaptor protein vinculin (VCL) and its interaction with ICAM-1 to reinforce VE-cadherin-actin junctions, suppress excessive leukocyte adhesion, and seal gaps in the alveolo-vascular barrier, thereby diminishing inflammatory exudation and lung edema seen in COVID-19151.
Possible treatments: anti-VCL monoclonal antibodies, vinculin-peptide competitors, small-molecule VCL-actin interface disruptors
427. TLR4 antagonism
Small-molecule or lipid-A analogues that prevent spike-S1 engagement of toll-like receptor-4, dampening early MyD88→NF-κB cytokine release and subsequent hyper-inflammation20,127,134,138,147 .
Possible treatments: eritoran, resatorvid, Jinhong decoction, rhubarbic acid
428. Gasdermin-D pore inhibition (anti-pyroptosis)
Small molecules or peptides that prevent GSDMD cleavage/oligomerisation may stop pyroptotic pore formation, lowering IL-1β release and the downstream cytokine-storm cascade66,68,131,147 .
Possible treatments: disulfiram, necrosulfonamide, dimethyl fumarate
429. Gasdermin-E (GSDME) inhibition (anti-pyroptosis)
Inhibition of Gasdermin-E (GSDME) activation to prevent the pyroptotic cell death of multinucleated syncytia. Blocking this pathway may reduce the release of inflammatory mediators from fused cells and limit subsequent tissue damage21.
Possible treatments: GSDME inhibitors, pan-caspase inhibitors (to block GSDME cleavage)
430. HIF-1α inhibition
Block hypoxia-driven metabolic re-programming that fuels NET formation and cytokine surges in severe COVID-195,33,58,100,103,138 .
Possible treatments: PX-478, digoxin, acriflavine, Jinhong decoction
431. RAGE antagonism
Interrupt AGE/RAGE signaling linked to TNF-α amplification and endothelial dysfunction in advanced disease103.
Possible treatments: azeliragon, FPS-ZM1, alagebrium
432. GPR4 (proton-sensing GPCR) antagonism
Antagonists of endothelial GPR4 blunt leukocyte adhesion, chemokine/cytokine release and COX-2 induction, thereby mitigating cytokine-storm-driven lung injury119.
Possible treatments: NE-52-QQ57, imidazopyridine GPR4 antagonist series
433. CXCL10 (IP-10) / CXCR3 axis blockade
Neutralizing the chemokine CXCL10 (also called IP-10) or inhibiting its receptor CXCR3 limits the chemo-attraction of activated T cells and monocytes into lung tissue, tempering the hyper-inflammation and tissue damage seen in severe COVID-19116,121,135 .
Possible treatments: AMG 487, BMS-936557, ipiliximab, NI-0801, elipovimab, KVX-053
434. Omega-3 / SPM
Eicosapentaenoic and docosahexaenoic acids give rise to resolvins/protectins that improve resolution of post-viral lung inflammation and may lessen long-COVID pathology17,90.
Possible treatments: EPA, DHA, protectin D1, resolvin D1
435. ERK/JNK/p38 MAPK pathway inhibition
Inhibiting the MAPK cascade downstream of spike-TLR signaling suppresses NLRP3 activation and cytokine release in lung epithelium, minimizing post-COVID inflammatory damage19,58,83,91,98,132,148 .
Possible treatments: luteolin, SB203580, selumetinib, Harrisonia perforata, losmapimod, SB203580, doramapimod
436. Extracorporeal cytokine adsorption
Physical removal of excessive cytokines from blood using adsorption columns to rapidly reduce cytokine storm severity in critically ill patients10.
Possible treatments: CytoSorb, oXiris, Toraymyxin
437. AHR-mucin (MUC5AC/MUC5B) suppression
AHR activation in airway epithelium drives goblet-cell differentiation and MUC5AC/MUC5B expression with mucus hypersecretion; AHR modulation can normalise mucus output and airflow57,58.
Possible treatments: CH-223191, GNF351, tapinarof
438. NLRP12 cleavage suppression
3CLpro cleaves NLRP12, a negative regulator of NLRP3, thereby amplifying cytokine production; preserving NLRP12 function may temper hyperinflammation68.
Possible treatments: NLRP12-stabilizing peptides, cleavage-site blockers, small-molecule NLRP12 agonists
439. P-selectin-PSGL-1 (SELPLG) leukocyte adhesion blockade
Blocking endothelial/platelet P-selectin binding to SELPLG (PSGL-1) limits rolling/adhesion and immune-cell influx into inflamed tissues134.
Possible treatments: crizanlizumab (anti-P-selectin), rivikizumab/anti-PSGL-1 candidates, rivipansel (GMI-1070; selectin antagonist)
440. Leukotriene receptor antagonism
Blocking the action of leukotrienes, which are inflammatory mediators involved in the pathogenesis of ARDS. This may help reduce lung inflammation and tissue damage5,17,28 .
Possible treatments: montelukast, pranlukast
441. Vascular Endothelial Growth Factor (VEGF) inhibition
Blocking VEGF signaling to reduce virus-induced angiogenesis, vascular permeability, and pulmonary edema associated with severe ARDS5.
Possible treatments: bevacizumab, tivozanib
442. NLRP12 cleavage suppression
The main protease (3CLpro/Mpro) cleaves NLRP12, a negative regulator of the NLRP3 inflammasome and NF-κB signaling. By disabling this immune checkpoint, the virus can dysregulate the inflammatory response. Preserving NLRP12 function may help temper hyperinflammation68.
Possible treatments: NLRP12-stabilizing peptides, cleavage-site blockers, small-molecule NLRP12 agonists
443. IL-18 pathway blockade
Neutralize IL-18 or block IL-18R to minimize inflammasome-driven lung inflammation and pyroptosis123,147.
Possible treatments: tadekinig alfa (IL-18BP), GSK1070806, anti-IL-18R agents
444. NOX4 (NADPH oxidase-4) inhibition
Possible treatments: setanaxib (GKT137831), apocynin, DPI
445. Caspase-1 → IL-18 maturation blockade
Block caspase-1 to curb processing of pro-IL-18/pro-IL-1β and downstream pyroptosis147.
Possible treatments: belnacasan (VX-765), Z-YVAD-FMK
446. SERPINA3 (α1-antichymotrypsin) augmentation
SERPINA3 is an acute-phase serine-protease inhibitor. Augmenting SERPINA3 activity could help restrain neutrophil/chymase proteolysis and downstream inflammation91.
Possible treatments: recombinant SERPINA3, serpin mimetics (experimental)
447. TP53 stabilization inhibition in syncytia
Inhibiting the stabilization of TP53 (p53) that occurs following spike-mediated cell-cell fusion. This stabilization is linked to pro-inflammatory cytokine release and cellular senescence, so its blockade may reduce syncytia-driven pathology21.
Possible treatments: TP53 stabilization inhibitors
448. Caspase-3 inhibition for neuroprotection
Blocking the activation of cleaved caspase-3 in infected astrocytes. This pathological apoptosis is driven by a pro-inflammatory response and contributes to cell death and neuroinflammation38.
Possible treatments: pan-caspase inhibitors, Z-DEVD-FMK
449. Astrocytic EAAT1/EAAT2 upregulation
SARS-CoV-2 lowers astrocyte EAAT1 (GLAST) and EAAT2 (GLT-1), impairing glutamate uptake and creating neuroinflammation/headache/brain fog. Boosting EAAT1/2 restores synaptic glutamate clearance and dampens downstream cytokines38.
Possible treatments: ceftriaxone, β-lactam class, riluzole, N-acetylcysteine, propentofylline
450. AKT1 signaling restoration
Restoring AKT1 signaling, which is significantly downregulated in severe COVID-19, to reduce neutrophil recruitment, prevent acute lung injury, and support BCL2-mediated lymphocyte survival138.
Possible treatments: Jinhong decoction, AKT1 activators
451. ICAM-1 expression suppression
Downregulating Intercellular Adhesion Molecule 1 (ICAM-1), which is overexpressed during cytokine storms, to reduce endothelial damage and leukocyte infiltration into lung tissue138.
Possible treatments: Jinhong decoction, rhubarbic acid
452. Histamine H2 receptor antagonism
The H2 blocker famotidine is identified as a top compound interacting with ferroptosis-related genes in COVID-19 cardiac tissue. Beyond acid suppression, it may reduce oxidative stress, maintain cardiac stem cell populations, and decrease cytokine release62.
Possible treatments: famotidine
453. PPAR-α activation
Peroxisome Proliferator Activated Receptor Alpha (PPARA) is identified as a central hub gene in COVID-19 heart tissue involved in lipid metabolism. Its downregulation correlates with ferroptosis and cardiac injury; agonists may restore metabolic homeostasis and inhibit inflammation17,62.
Possible treatments: fenofibrate, gemfibrozil, pemafibrate
454. PRC1 (Protein Regulator of Cytokinesis 1) targeting
PRC1 is a microtubule-associated protein and hub gene dysregulated in COVID-19. Transcriptomic analysis links its expression to lung fibrosis disorders (e.g., silicosis), suggesting it contributes to the fibrotic sequelae of severe SARS-CoV-2 infection116.
455. Cellular senescence pathway (CDKN2A/p16) modulation
Transcriptomic enrichment shows significant upregulation of the cellular senescence pathway, specifically the marker CDKN2A (p16), in infected lungs. Senescent cells secrete pro-inflammatory factors (SASP); senolytics could mitigate this chronic inflammatory drive116.
Possible treatments: navitoclax, fisetin, quercetin, dasatinib
456. TNFR1 signaling inhibition
Targeting Tumor Necrosis Factor Receptor 1 (TNFR1), which is significantly upregulated in SARS-CoV-2 associated myocarditis. Excessive TNFR1 signaling drives oxidative stress, endothelial dysfunction, and necroinflammatory lesions; blocking this pathway may prevent the transition to chronic myocardial injury46.
Possible treatments: TNFR1 antagonists, TNF inhibitors
457. CXCL16 axis blockade
Targeting the chemokine CXCL16, identified as a key biomarker in COVID-19 associated acute kidney injury (AKI) that correlates with immunometabolic collapse and severity. Inhibition of the CXCL16/CXCR6 axis may limit renal inflammation and tissue damage46.
Possible treatments: anti-CXCL16 antibodies
458. ACSL4 (Acyl-CoA Synthetase Long-Chain Family Member 4) inhibition
ACSL4 enriches cellular membranes with long-chain polyunsaturated fatty acids (PUFAs), which are the primary substrates for lipid peroxidation. The Spike protein triggers the ferroptotic pathway where ACSL4 facilitates the formation of toxic lipid-ROS; inhibiting ACSL4 prevents the execution of ferroptosis52.
Possible treatments: rosiglitazone, troglitazone, pioglitazone, ACSL4-specific inhibitors (PRGL493)
459. GPx4 (Glutathione Peroxidase 4) activation
GPx4 is the primary enzymatic "brake" on ferroptosis, reducing toxic lipid hydroperoxides to alcohols. Spike protein exposure disrupts GPx4 levels in a brain-region-specific manner. Preserving GPx4 activity or selenium levels is critical to preventing Spike-induced neurodegeneration52.
Possible treatments: selenium, N-acetylcysteine, liproxstatin-1, ferrostatin-1, glutathione precursors
460. Angiotensin II Type 1 Receptor (AT1R) blockade (Ferroptosis axis)
SARS-CoV-2 binding degrades ACE2, leading to Angiotensin II accumulation. Ang II activates AT1R, stimulating NADPH oxidase (NOX) to produce ROS, which drives lipid peroxidation and ferroptosis. Blocking this axis mitigates the oxidative cascade triggered by Spike-ACE2 interaction52.
Possible treatments: losartan, valsartan, telmisartan, candesartan
461. NOSTRIN-eNOS axis restoration
Identified as a top downregulated regulator in COVID-19 airway epithelium. NOSTRIN modulates eNOS activity; suppression leads to reduced nitric oxide production, exacerbating endothelial dysfunction, thrombosis, and lung inflammation89,98.
Possible treatments: inhaled nitric oxide, NO donors, L-arginine, eNOS enhancers
462. CHUK (IKKα) inhibition
The Conserved Helix-Loop-Helix Ubiquitous Kinase (CHUK/IKKα) is identified as a top upregulated regulator in the upper airway. It drives the canonical NF-κB pathway, leading to cytokine storm and ARDS98.
Possible treatments: IKK inhibitors, BMS-345541, TPCA-1
463. PDGFRB signaling modulation
PDGFRB is identified as a gene with significant differential methylation (hypo- and hypermethylated sites) in COVID-19 patients. Dysregulated PDGF signaling is a key driver of tissue remodeling and pulmonary fibrosis in post-acute sequelae98.
Possible treatments: nintedanib, imatinib, sunitinib, sorafenib
464. MMP1 (Matrix metalloproteinase-1) inhibition
MMP1 is a shared pathogenic hub gene upregulated in severe COVID-19, particularly in B cells and plasma cells. Inhibiting MMP1 directly reduces the infiltration of neutrophils into tissues, thereby dampening hyperinflammation and preventing tissue damage109.
Possible treatments: colchicine
465. Necroptosis inhibition (RIPK1/RIPK3/MLKL blockade)
Blocking RIPK1/RIPK3 kinase activity or downstream MLKL oligomerization to prevent necroptosis. This stops the lytic destruction of alveolar epithelial cells and the subsequent release of pro-inflammatory DAMPs71.
Possible treatments: Nec-1s, RIPK1 inhibitors, RIPK3 inhibitors, MLKL inhibitors
466. P2X7 receptor antagonism
Hyperactivation of the P2X7 receptor by extracellular ATP triggers NLRP3 inflammasome activation and neuroinflammation. Antagonists can reduce microglial activation and neurobehavioral deficits132.
Possible treatments: P2X7 antagonists, JNJ
467. Gasdermin B (GSDMB) airway inflammation modulation
GSDMB mediates inflammatory responses in the airway following viral infection via MAVS-TBK1 signaling. Genetic and splicing association analyses demonstrate GSDMB is a shared genetic factor between COVID-19 hospitalization and COPD, driving hyperinflammatory airway responses40.
Possible treatments: GSDMB inhibitors, GSDMB splicing modulators
468. ArfGEF1/ArfGAP1-mediated Golgi-mitochondria disruption
The viral M protein interacts with host regulatory factors ArfGEF1 and ArfGAP1 in the Golgi apparatus, promoting pathological retrograde transport to the ER. This induces mitochondrial fragmentation and functional impairment (decreased ATP, excess ROS), leading to caspase-associated cell death and neurodegeneration31.
469. SREBP-2/NF-κB inflammatory crosstalk blockade
SARS-CoV-2 infection activates SREBP-2, which disturbs cholesterol biosynthesis and triggers a cytokine storm. SREBP-2 activity is regulated by crosstalk between cholesterol consumption and NF-κB expression via inflammatory response processes induced by infection. The selective RARα agonist AM580 strongly inhibits coronavirus replication by interacting with SREBP-2, representing a broad-spectrum lipidomic reprogramming target17.
Possible treatments: AM580, fatostatin, betulin, PF-429242
470. AP-1 transcription factor complex inhibition
SARS-CoV-2 infection strongly upregulates the AP-1 transcription factor complex to drive stress-induced reprogramming, cellular senescence, and hyperinflammation. Inhibiting AP-1 activation can mitigate virus-induced cellular stress pathways and pro-inflammatory cytokine release118.
Possible treatments: T-5224, SR11302
471. Thymidine phosphorylase (TYMP) inhibition
SARS-CoV-2 spike protein induces sustained TYMP expression, which amplifies STAT3-mediated inflammation, microthrombus formation, and fibrotic remodeling. This TYMP-dependent mechanism creates a myeloid-dominated microenvironment conducive to malignant transformation and significantly increases lung cancer risk. Inhibiting TYMP may prevent post-COVID fibrosis and mitigate cancer risk136.
Possible treatments: tipiracil
472. Microglial Kv1.3 channel inhibition
The SARS-CoV-2 Spike protein S1 subunit increases the activity of Kv1.3 channels in microglia, driving microglial activation, the release of proinflammatory cytokines, and anxiety- or depression-like behaviors. Inhibiting this channel mitigates these neuroinflammatory and behavioral effects11.
Possible treatments: chlorpromazine, PAP-1
Complement System Regulation
Mechanisms that control excessive complement activation, which contributes to inflammation.
473. Complement pathway inhibition
Possible treatments: eculizumab, ravulizumab, coversin, zilucoplan, cemdisiran, tesidolumab
474. C3 inhibition
Possible treatments: pegcetacoplan, AMY-101
475. C2 inhibition (classical / lectin pathway)
Monoclonal antibodies that bind complement factor C2 prevent C3 pro-convertase assembly, selectively shutting down classical and lectin amplification while sparing the alternative pathway.
Possible treatments: empasiprubart (ARGX-117)
476. Classical pathway inhibition
Blocking C1 esterase or C1s to suppress classical pathway activation44.
Possible treatments: cinryze, sutimlimab, ruconest
477. C5a signaling blockade
Targeting C5a or its receptor to reduce inflammatory anaphylatoxin effects133.
Possible treatments: vilobelimab, avdoralimab, IFX-1, NOX-D21
478. Alternative pathway inhibition
Inhibiting Factor B to disrupt alternative pathway amplification.
Possible treatments: iptacopan, LNP023
479. Alternative pathway suppression
Blocking Factor D to halt alternative pathway activation.
Possible treatments: danicopan, ACH-4471
480. Lectin pathway inhibition
Targeting MASP-2 to inhibit lectin pathway initiation.
Possible treatments: narsoplimab, OMS721
481. Targeted complement regulation
Fusion protein to inhibit complement at sites of activation.
Possible treatments: TT30
482. Broad-spectrum inhibition
Recombinant soluble complement receptor 1 (sCR1) for multi-pathway suppression.
Possible treatments: TP10
483. C3a signaling blockade
Neutralizing C3a or antagonizing C3aR diminishes complement-induced platelet activation and microvascular thrombosis133.
Possible treatments: anti-C3a mAb, SB-290157, PMX-53
Apoptosis & Viral Clearance
Mechanisms that promote the elimination of infected cells or viral components.
484. Apoptosis induction
Possible treatments: venetoclax, navitoclax, obatoclax, gossypol, busulfan, carboplatin, cisplatin, ifosfamide, etopophos
485. Extrinsic apoptosis activation
Activating TRAIL death receptors to induce apoptosis in infected cells.
Possible treatments: conatumumab, dulanermin
486. Fas-mediated apoptosis
Stimulating Fas receptors to trigger caspase-dependent cell death.
Possible treatments: APG101, fas_antibody
487. IAP inhibition
Promoting apoptosis by antagonizing inhibitor of apoptosis proteins (IAPs).
Possible treatments: birinapant, LCL161
488. p53 activation
Possible treatments: nutlin-3a, PRIMA-1MET
489. Autophagy stimulation
Enhancing mTOR-independent/AMPK-mediated degradation of viral components.
Possible treatments: rapamycin, everolimus, spermidine, resveratrol, metformin, trehalose
490. Efferocytosis enhancement
Promoting phagocytic clearance of apoptotic cells containing viral material.
Possible treatments: annexin_A1, resolvin_E1, meritastat
491. Immunogenic cell death
Inducing apoptosis with enhanced antigen presentation for immune clearance.
Possible treatments: oxaliplatin, doxorubicin
492. PINK1/Parkin-mediated mitophagy enhancement
Boost clearance of damaged mitochondria via PINK1/Parkin to lower mtROS and downstream inflammatory signaling103.
Possible treatments: urolithin A, nicotinamide riboside, CNX-074
493. Selective virophagy receptor protection (p62/SQSTM1-NBR1-Galectin-8/NDP52 axis)
3CLpro cleaves p62/SQSTM1 (Q354), NBR1 (Q353, in PEDV) and Galectin-8 (Q158), blocking selective autophagic clearance of viral proteins. Preserving these receptors or enhancing their cargo-linking restores virophagy31,66.
Possible treatments: Tat-LIR mimetic peptides that stabilize LC3-receptor binding, Galectin-8-NDP52 interface enhancers
494. Selective virophagy receptor protection (p62/SQSTM1)
The viral main protease (3CLpro/Mpro) cleaves the autophagy receptor p62/SQSTM1 at Q354. This disables p62's ability to traffic viral proteins (like the M protein) to autophagosomes for degradation, thus protecting virion components and ensuring successful assembly. Protecting p62 from cleavage could restore this host defense mechanism68.
Possible treatments: p62 cleavage-site blockers, Tat-LIR mimetic peptides that stabilize LC3-receptor binding
495. MCL1 (Myeloid Cell Leukemia 1) inhibition
MCL1 is an anti-apoptotic protein found to be upregulated and raft-associated during viral protein expression. Induction of MCL1 likely delays host cell apoptosis to prolong the window for viral replication and assembly. Inhibition could restore apoptotic clearance of infected cells39.
Possible treatments: S63845, AMG-176, AZD5991, mimetics
496. PDPK1/SQSTM1-mediated mitophagy modulation
The viral M protein promotes mitochondrial autophagy (mitophagy) to suppress type I interferon responses via PDPK1-mediated phosphorylation of the host autophagy cargo receptor SQSTM1 (p62). Peptides targeting PDPK1 can redirect SQSTM1 from the M protein back to mitochondria, counteracting this virus-induced mitophagy and restoring viral clearance31.
Possible treatments: PDPK1-targeted peptides
497. M protein-induced BOK apoptosis blockade
The SARS-CoV-2 M protein triggers mitochondrial apoptosis in pulmonary epithelial cells by engaging BCL-2 ovarian killer (BOK) in a caspase-9-dependent manner. This leads to caspase-associated cell death and increased pulmonary barrier permeability. The M protein also suppresses PKB/Akt phosphorylation, downregulating pro-survival signaling and activating both caspase-8 and caspase-9. Blocking this pathway may preserve alveolar barrier integrity and reduce pulmonary edema31.
Possible treatments: BOK inhibitors, Akt activators, caspase-9 inhibitors, Z-LEHD-FMK
Host Nutrient & Factor Modulation
Mechanisms aimed at manipulating the availability or metabolism of host-derived nutrients and factors essential for viral replication or survival.
498. Angiotensin-(1-7) / Mas-receptor agonism
Exogenous Ang(1-7) or small-molecule Mas agonists restore the protective ACE2-Ang(1-7)-Mas arm of RAAS that is lost after spike-induced ACE2 internalisation, delivering vasodilatory, anti-thrombotic, anti-fibrotic and anti-inflammatory effects that can mitigate ARDS, endothelial dysfunction and long-COVID sequelae146.
Possible treatments: Angiotensin-(1-7) peptide, TXA-127, AVE0991, CGEN-856, CGEN-856S
499. Arginine depletion therapy
Pegylated arginase I lowers extracellular arginine, reducing NO-driven hyper-inflammation and starving viral polyamine synthesis pathways implicated in severe COVID-1990.
Possible treatments: PEG-Arg1 (pegylated arginase I)
500. Polyamine synthesis inhibition
Blocking polyamine synthesis pathways that viruses exploit for replication. SARS-CoV-2 requires polyamines for RNA synthesis and protein translation10,82.
Possible treatments: difluoromethylornithine (DFMO), SAM486A
501. MTR (methionine synthase)/vitamin B12 axis modulation
Predicted host factor MTR links one-carbon metabolism to SAM availability for viral RNA capping/methylation; modulating the B12-MTR cycle may perturb pro-viral methyl flux44.
Possible treatments: cyanocobalamin
502. Biotinidase (BTD) / biotin-metabolism modulation
BTD is a plasma enzyme that recycles biotin; research identifies BTD as a top diagnostic biomarker and shows pathway enrichment in biotin metabolism, suggesting a nutrient-immune axis worth targeting91.
Possible treatments: biotin (clinical formulations), BTD inducers/replacement (experimental)
503. APOE modulation
Targeting APOE, which is involved in lipid metabolism and immune regulation. APOE modulates blood coagulation and immune response34.
Possible treatments: AEM-28, statins
504. APP inhibition
Inhibition of APP, which interacts with APOE and plays a role in neuroinflammation and immune dysregulation in COVID-19 patients. APP-targeting strategies could help mitigate immune and systemic disturbances in both acute and long COVID34,55.
Possible treatments: lecanemab, anti-APP antibodies, inositol
505. Pyridoxal 5'-phosphate supplementation
PLP (the active form of Vitamin B6) is a top metabolite linked to ferroptosis-related genes. It alleviates myocardial injury by inhibiting ferroptosis and apoptosis, specifically through the activation of the Nrf2 antioxidant pathway62.
Possible treatments: pyridoxal 5'-phosphate, vitamin B6
506. Neuropathogenic protein aggregation inhibition (⍺-synuclein/Tau)
SARS-CoV-2 infection induces hyperphosphorylation of Tau and somatic mislocalization in neurons, contributing to neurodegeneration. S1 protein also seeds ⍺-synuclein aggregation33,100.
Possible treatments: metformin
507. Synaptic plasticity gene restoration (GRIN2A/JPH3)
SARS-CoV-2 S1 protein downregulates critical synaptic plasticity genes, including GRIN2A (NMDA receptor subunit), JPH3, and SHANK1, via HIF-1⍺ stabilization. Restoring the expression of these genes prevents dendritic collapse and rescues cognitive function100.
Possible treatments: metformin
508. HIF-1α SUMOylation blockade
SARS-CoV-2 S1 promotes the SUMOylation of HIF-1⍺, leading to its stabilization under normoxic conditions in the brain. Blocking this SUMOylation pathway facilitates HIF-1⍺ degradation and protects against synaptic dysfunction100.
Possible treatments: metformin
509. Metallothionein 2A (MT2A) modulation
MT2A is a cysteine-rich, intracellular zinc-buffering protein that links zinc dysregulation to redox signaling and immunopathology. High MT2A expression in myeloid cells correlates with COVID-19 mortality and co-regulates with viral entry factors and inflammatory cytokines. Targeting MT2A may restore zinc-dependent immune signaling thresholds24.
Possible treatments: MT2A degraders (PROTACs), siRNA-MT2A, phi29 pRNA-siRNA chimeras, zinc supplementation (upstream modulator)
510. DMT1 (Divalent Metal Transporter 1) inhibition
DMT1 mediates the cellular uptake of ferrous iron. The SARS-CoV-2 Spike protein S1 subunit significantly upregulates DMT1, driving an expanded labile iron pool, oxidative stress, and subsequent ferroptosis in neuronal tissues52.
Possible treatments: ebselen, iron chelators, DMT1 inhibitors
511. Ferroportin (FPN1) stabilization
FPN1 is the only known mammalian cellular iron exporter. Spike protein exposure alters FPN1 expression in the brain as a potential compensatory response to iron overload. Enhancing or stabilizing FPN1 function facilitates iron efflux and prevents ferroptotic cell death52.
Possible treatments: ferroportin stabilizers, anti-hepcidin agents
512. Hemoglobin-Spike interaction blockade
Blocking the direct interaction between SARS-CoV-2 Spike protein (via Asn/Cys residues) and host hemoglobin, which disrupts hemoglobin structure/function and contributes to hypoxia and RBC damage16.
Possible treatments: L-asparaginase, tryptanthrin, kaempferol
513. IGF-1 signaling modulation
Identified as a central node in the epigenetic regulatory network of COVID-19 airways. While IGF-1 is crucial for tissue repair, overactivation or dysregulation is linked to pathological pulmonary fibrosis in severe and long COVID98.
Possible treatments: IGF-1 pathway modulators
Immune Evasion Countermeasures
Mechanisms that counteract SARS-CoV-2's ability to suppress host immunity.
514. Viral immune modulation inhibition
Blocking viral proteins that suppress host immunity.
515. ORF9b-TOM70 interface blockade
Disrupt ORF9b binding to the C-terminus of TOM70 to restore HSP90-mediated MAVS signaling, type-I interferon output and balanced mitochondrial metabolism34,103.
Possible treatments: peptidomimetic C-tail competitors, macrocyclic PPI inhibitors, HSP90-TOM70 stapled-peptides
516. Restoring interferon signaling
Countering viral antagonism of STAT1/IRF pathways to reinstate endogenous interferon responses34,57,58,66,68,75,83,85,87,101,103 .
Possible treatments: interferon-beta
517. NSP3 deubiquitinase inhibitors
Blocking NSP3's immune evasion via deubiquitinase activity70.
Possible treatments: acriflavine, YM155, GRL0617, XR-8-24
518. NSP3-IFIT5/ISG15 axis disruption
Small molecules or peptides that block NSP3-mediated de-ISGylation of IFIT5, restoring ISG15-dependent IRF3/NF-κB signaling and type I-IFN output145.
Possible treatments: IFIT5-interface mimetics, NSP3 macrodomain blockers
519. ORF6 protein inhibitors
Neutralizing ORF6-mediated interferon suppression103.
520. NSP1 translation inhibition
Preventing NSP1 from blocking host translation.
521. Wnt / β-catenin pathway inhibition & peroxisome restoration
SARS-CoV-2 activates Wnt / β-catenin signaling to deplete peroxisomes and blunt MAVS-mediated type I/III IFN production. Small-molecule Wnt/β-catenin antagonists reverse this immune-evasion tactic by restoring peroxisome biogenesis, amplifying innate IFN responses and sharply lowering viral replication in airway cells and mouse lungs152.
Possible treatments: KYA1797K, IWP-O1, LGK-974, Wnt-C59, NCB-0846, ETC-1922159, Pyrvinium, E7449, iCRT-14, SM04690
522. Nsp9-mediated suppression of extracellular let-7b & TLR7 signaling
SARS-CoV-2 Nsp9 binds let-7b, loads it into AGO2, and blocks its packaging into exosomes, sharply lowering extracellular let-7b that would otherwise activate TLR7 and drive type-I interferon/cytokine induction. Countermeasures aim to disrupt the Nsp9-let-7b interface or supply exogenous let-7b to restore TLR7 antiviral signaling80.
Possible treatments: let-7b mimics, exosome-loaded let-7b, inhibitors of Nsp9-let-7b binding, TLR7 agonists
523. Nucleocapsid-G3BP interface blockade
Small molecules or peptides that occupy the NTF2-groove of G3BP1/2 or mask N residues I15-G18, preventing N-mediated stress-granule dissolution and restoring PKR/IFN signaling101,106.
Possible treatments: macrocyclic PPI inhibitors, N-terminal decoy peptides, groove-filling hetero-bicycles
524. Nsp14-mediated lysosomal downregulation of IFNAR1/IFNGR1
SARS-CoV-2 Nsp14 reduces surface IFNAR1 and IFNGR1 through a lysosomal pathway, blunting IFN-α/β and IFN-γ signaling. Effects are evident in infected cells and with Nsp14 expression; IFNAR2 is spared. Countermeasures aim to preserve receptor abundance or block lysosomal routing83.
Possible treatments: bafilomycin A1, lysosome-trafficking inhibitors, siRNA-TOLLIP, IFNAR1/IFNGR1 endocytosis-blockers
525. Nsp14-driven NF-κB/ERK/JNK/p38 activation (N7-MTase-dependent)
Nsp14 augments NF-κB and activates ERK, JNK and p38 MAPKs, promoting cytokine output (IL-1β, IL-6, IL-10, CXCL10/CCL4/CCL5). ExoN-dead mutants largely retain activity, whereas N7-MTase-dead mutants lose it. Targeting Nsp14's MTase function or downstream kinases can curb this pro-inflammatory signaling83.
Possible treatments: MEK inhibitors (selumetinib, trametinib), p38 inhibitors (losmapimod), IKK/NF-κB pathway inhibitors, N7-MTase inhibitors (sinefungin-class/analogs)
526. N-protein cleavage by caspase-6 (IFN suppression) - countermeasure
During infection, activated caspase-6 cleaves N; resulting fragments dampen IRF3/IFN-I signaling and aid replication. Lowering CASP6 abundance (mRNA destabilisation) or inhibiting its activity reduces cleaved-N, reverses IFN suppression, and limits viral growth75.
Possible treatments: dibenzoylmethane, Z-VEID-FMK, caspase-6 inhibitors
527. RLR/NEMO axis preservation from 3CLpro antagonism
The SARS-CoV-2 main protease (3CLpro/Mpro) dismantles the RIG-I-like receptor (RLR) pathway by cleaving RIG-I, promoting MAVS degradation, and cleaving the essential adaptor NEMO. This collective antagonism suppresses type I interferon production. Therapeutics may protect these components or otherwise restore the pathway's function66,68.
Possible treatments: 5'ppp-dsRNA RIG-I agonists, cell-permeable NEMO-derived decoy peptides, protein-protein interface stabilizers
528. Hippo signaling pathway activation
Activation of the evolutionarily conserved Hippo signaling pathway, which contributes to the host's intrinsic antiviral response during SARS-CoV-2 infection112.
529. Blockade of Nsp5-driven MAVS SUMOylation → NF-κB hyperactivation
SARS-CoV-2 Nsp5 increases SUMOylation of MAVS, boosting NF-κB signaling; disrupting SUMOylation or enhancing de-SUMOylation can restore balanced IFN/NF-κB responses58.
Possible treatments: subasumstat (TAK-981; SUMO-E1 inhibitor), SENP modulators
530. ORF10-driven innate-immune attenuation
ORF10 remodels host transcription with reduced oxidative phosphorylation and suppression of interferon/stress-response genes, weakening antiviral signaling. Therapeutic approaches aim to restore IFN/MAVS activity and mitochondrial tone alongside direct ORF10 blockade87.
Possible treatments: interferon-β/interferon-λ, STING or RIG-I agonists, SS-31, CoQ10, nicotinamide riboside
531. Nsp3 Mac1 (ADP-ribosylhydrolase) inhibition
The Nsp3 macrodomain (Mac1) removes mono-ADP-ribose (MAR) modifications from host proteins (catalyzed largely by PARP14), thereby reversing the host interferon-induced antiviral response. Small-molecule inhibition of Mac1 restores these immune marks, potentiates the innate immune response, and limits viral replication in vivo79.
Possible treatments: AVI-4206, AVI-4636, AVI-4051, AVI-219, AVI-92, GE-112, ADP-ribose analogs
532. DDX21 RNA helicase sequestration blockade
The SARS-CoV-2 N protein associates with the C-terminal domain of the host nucleolar helicase DDX21 in a phosphorylation-independent manner. Because DDX21 functions as a viral restriction factor involved in double-stranded RNA sensing and interferon induction, N protein binding likely sequesters DDX21 away from immune sensors to suppress host antiviral signaling. Small molecules that disrupt this interaction could restore host innate immune responses114.
Possible treatments: N-DDX21 interaction disruptors
533. IFNAR2 isoform regulation (alternative splicing)
Alternative splicing of the Type I interferon receptor subunit (IFNAR2) acts as a key genetic discriminator between severe COVID-19 and other respiratory conditions. Modulating the splicing machinery to favor protective IFNAR2 isoforms could restore localized antiviral interferon signaling40.
Possible treatments: splice-switching oligonucleotides targeting IFNAR2, IFNAR2 isoform-selective modulators
534. M protein-mediated MAVS/TBK1/IRF3 axis suppression
The viral Membrane (M) protein acts as a negative regulator of the host innate immune response by inhibiting the aggregation of MAVS. This specifically impairs the recruitment of downstream signaling molecules such as TRAF3, TBK1, and RIG-I, ultimately preventing the phosphorylation and nuclear translocation of IRF3 and suppressing type I and III interferon production31.
Viral Fusion Inhibition
Mechanisms that prevent viral membrane fusion with host cells.
535. FcγRI-mediated fusion blockade
Blocking the Fc-gamma receptor I (FcγRI) to prevent antibody-mediated, ACE2-independent cell-cell fusion (syncytia formation). This pathway can be triggered by certain anti-RBD antibodies and is implicated in antibody-dependent enhancement (ADE) and the formation of macrophage syncytia21.
Possible treatments: anti-FcγRI antibodies, Fc decoy proteins
536. IFITM1 activation
Enhancing the activity of interferon-induced transmembrane protein 1 (IFITM1), which is localized at the plasma membrane and exhibits a strong inhibitory effect on spike-mediated cell-cell fusion (syncytia formation), likely by modifying membrane rigidity21.
Possible treatments: IFITM1 activators
537. TNF/TNFR1 axis activation (early phase)
Early signaling through Tumor Necrosis Factor (TNF) and its receptor TNFR1 activates the TRADD/TRAF2/RIPK1-MAPK-SDC4 cascade, preventing SARS-CoV-2 spike-mediated cell-cell fusion. This represents a phase-specific antiviral role for TNF prior to late-stage hyperinflammation153.
Possible treatments: recombinant TNF, TNFR1 agonists
538. SDC4 (Syndecan-4) pathway activation
Activation or overexpression of the cell-surface proteoglycan Syndecan-4 (SDC4) promotes cytoskeletal reorganization. Acting downstream of TNF, SDC4 triggers actin bundle formation at the interface of infected and adjacent cells, creating a mechanical barrier against syncytia propagation153.
Possible treatments: SDC4 agonists
539. RhoA/ROCK-mediated actin remodeling
Activation of the RhoA/ROCK signaling pathway induces the accumulation of F-actin bundles at intercellular junctions, physically blocking Spike-mediated cell-cell fusion153.
Possible treatments: RhoA activators, ROCK activators
Antiviral Peptides
Mechanisms involving peptides that directly inhibit viral activity.
540. Defensins
Antimicrobial peptides with potential antiviral effects.
Possible treatments: Human neutrophil peptide-1 (HNP-1)
541. Fusion inhibitor peptides
Peptides blocking viral fusion with host membranes.
Possible treatments: EK1C4
542. Lactoferrin
Iron-binding protein with antiviral properties.
Possible treatments: bovine lactoferrin
543. Cathelicidin peptides
Antimicrobial peptide disrupting viral envelopes.
Possible treatments: LL-37
544. Hepcidin
Liver-produced peptide with immunomodulatory effects.
Possible treatments: hepcidin-25
545. TAT-based peptides
Cell-penetrating peptides disrupting viral assembly.
Possible treatments: TAT-SARS2
546. RBD-targeting antiviral peptides (InSiPS AVPs)
Synthetic 15-25-aa peptides designed in silico that bind conserved spike-RBD or S1/S2 motifs, out-compete ACE2, curb multivariant infection, and blunt pro-inflammatory cytokines145.
Possible treatments: InSiPS-AVP1, InSiPS-AVP2, InSiPS-AVP3
RNA Interference
Mechanisms that silence viral genes to inhibit replication.
547. siRNA therapy
Small interfering RNAs targeting viral genes.
Possible treatments: siRNA against RdRp
548. siRNA targeting spike
Silencing spike gene to prevent viral entry.
Possible treatments: siRNA-Spike
549. siRNA targeting nucleocapsid
Inhibiting nucleocapsid gene to disrupt virion formation.
Possible treatments: siRNA-N
550. shRNA therapies
Sustained gene silencing via short hairpin RNA.
Possible treatments: shRNA-ORF1ab
551. miRNA mimics
Using microRNAs to target viral RNA degradation.
Possible treatments: miR-23b
552. MicroRNA modulation of antiviral immunity
Use of miRNA mimics or inhibitors to regulate host gene expression and immune pathways, enhancing antiviral responses or suppressing viral replication. Specific miRNAs (e.g., miR-181, miR-874, miR-155, miR-27a) can amplify innate immune signaling or induce apoptosis in infected cells, while inhibition of others (e.g., miR-1290, miR-576) reduces viral replication or virus-induced damage80,95,154 .
Possible treatments: miR-181 mimic, miR-874 mimic, miR-155 mimic, miR-27a mimic, miR-1290 antagonist, miR-576 inhibitor, let-7b mimic
553. siRNA/ASO targeting ORF10 transcript
Silencing the ORF10 gene, whose transcript is highly structured and conserved. A synonymous change that perturbs ORF10 RNA structural dynamics is associated with milder COVID-19, implicating a functional RNA role independent of the protein; targeting the RNA should attenuate ORF10-linked virulence programs87.
Possible treatments: siRNA-ORF10, antisense oligonucleotides (ASOs)
554. miR-492 modulation
MicroRNA-492 is identified as a specific regulator in severe COVID-19 and acute kidney injury (AKI). Modulating its activity represents a potential therapeutic avenue for treating severe renal complications46.
Possible treatments: miR-492 inhibitors/antagomirs
555. ASO targeting the 5'-UTR (HuR-binding site)
Using antisense oligonucleotides (ASOs) to sterically block conserved host protein binding sites on the viral 5'-UTR. Specifically, blocking the HuR-binding site around the C241 position (using ASO5) prevents host factor recruitment (HuR and PTB) and effectively reduces viral RNA levels63.
Possible treatments: ASO5
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