COVID-19 treatment: mechanisms of action
COVID-19 involves the interplay of 300+ 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 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.
Possible treatments: bamlanivimab, casirivimab/imdevimab, tixagevimab/cilgavimab, regdanvimab, etesevimab, APN01, STI-4398, griffithsin, cyanovirin-N, RBD-binding antiviral peptides
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 binding.
Possible treatments: sotrovimab, VIR-7832
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 fusion2,3.
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 entry.
Possible treatments: 4A8, 4-8, DH1050, S2X333
5. Spike protein conformational stabilizers
Compounds that lock the spike protein in its pre-fusion conformation, preventing the structural changes required for membrane fusion4.
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
Blocking the fusion process of SARS-CoV-2 with host cells by targeting HR1/HR2 domains.
Possible treatments: EK1, IPB02, EK1C4, HR2P
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 fusion5,6.
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 entry2.
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 entry7.
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 state4.
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 RBD4.
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 infectivity8.
Possible treatments: 2-bromopalmitate, TVB-2640 (FASN inhibitor)
Targeting Host Proteins/Factors
Entry inhibition mechanisms targeting host proteins/factors.
14. TMPRSS2 inhibition
Possible treatments: camostat, nafamostat, bromhexine, gabexate mesylate, N-0385, Scutellaria barbata
15. ACE2 modulation
Possible treatments: lisinopril, losartan, valsartan, enalapril, telmisartan, resveratrol, berberine, estradiol, melatonin, artefenomel, quercetin, fosinopril, aliskiren
16. 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 entry.
Possible treatments: recombinant human ACE2 (rhACE2), ACE2-Fc fusion proteins
17. Heparan sulfate mimicry
Possible treatments: heparin, heparan sulfate mimetics, carrageenan, fucoidan, pentosan polysulfate, necuparanib, PG545
18. Cathepsin L inhibition
Possible treatments: teicoplanin, MDL-28170, E-64d (aloxistatin)
19. Integrin targeting
Block integrin receptors - especially α2β1 (ITGA2) and α5β1, αvβ3 - involved in ACE2-independent entry11.
Possible treatments: cilengitide, SB273005, RGD peptide inhibitors, anti-ITGA2 antibodies, obtustatin, dioscin, natalizumab
20. 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 neuroinflammation8,11,13 .
Possible treatments: EG00229, soluble VEGF-A165b, VEGF-A inhibitors, meclizine, siRNA-NRP1
21. Lipid raft disruption
Deplete membrane cholesterol to destabilize lipid raft-dependent entry mechanisms2.
Possible treatments: simvastatin, fluvastatin, methyl-β-cyclodextrin, 25-hydroxycholesterol
22. Surfactant inactivation
Disrupt viral envelopes or spike-receptor interactions via surfactant activity.
Possible treatments: poloxamers, chlorhexidine
23. Inhibition of clathrin-mediated endocytosis or endosomal acidification
Inhibit clathrin-mediated endocytosis or endosomal acidification to prevent viral internalization2,6.
Possible treatments: chloroquine, hydroxychloroquine, dynasore, mitmab, bafilomycin A1, umifenovir
24. Furin inhibition
Possible treatments: decanoyl-RVKR-chloromethylketone, MI-1851, naphthofluorescein
25. 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 replication14,15.
Possible treatments: lapatinib, AG879, CP-724714
26. 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 cells8,11,16 .
Possible treatments: bemcentinib (BGB-324), gilteritinib, cabozantinib, soluble AXL protein, recombinant NTD protein
27. CD147 (Basigin) antagonism
Monoclonal antibodies or peptides block CD147/Basigin (a glycoprotein exploited for viral docking in some epithelia) thereby hindering spike-driven attachment and internalisation6,8,11,16 .
Possible treatments: meplazumab, anti-CD147 peptide decoys
28. 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 route8,11,16 .
Possible treatments: anti-KREMEN1 mAb, anti-ASGR1 mAb, ASGR1-Fc decoys, siRNA-KREMEN1/ASGR1, cocktail antibodies targeting ASK receptors
29. 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 step8,11,16,17 .
Possible treatments: polyman-26, glycodendrimers, anti-DC-SIGN mAb, griffithsin, cyanovirin-N, mannan, fucoidans, lectin inhibitors
30. 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 neutralising antibodies reduce infection8,11.
Possible treatments: BLT-1, ITX5061, anti-SR-B1 mAb
31. 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 endocytosis11.
Possible treatments: anti-KIM-1 mAb, KIM-1-competitive peptides, siRNA-KIM1
32. 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 variants8,18,19 .
Possible treatments: apilimod, UNI418, YM-201636, WX8-125
33. 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 strains20.
Possible treatments: UNC0642, UNC0638, BIX01294
34. MET (c-Met/HGFR) receptor inhibition
Blocking MET tyrosine-kinase disrupts coronavirus internalization and early replication steps, capmatinib shows broad anti-CoV activity in vitro15.
Possible treatments: capmatinib, tepotinib, crizotinib
35. 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 cells21.
Possible treatments: PB125, dimethyl fumarate, sulforaphane
36. 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 models2,8,10 .
Possible treatments: niclosamide, clofazimine, fluoxetine
37. 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 injury8,11.
Possible treatments: anti-TfR antibodies, TfR-competitive peptides, transferrin-derived blocking agents
38. 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 diabetes11.
Possible treatments: sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin
39. 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 infection11.
Possible treatments: myosin inhibitors, blebbistatin, 2, 3-butanedione monoxime
40. 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 efficacy11.
Possible treatments: HA15, kifunensine, GRP78 antagonists
41. 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 reactions11.
Possible treatments: TTYH2 antagonists, chloride channel blockers
42. 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 intervention11.
Possible treatments: PS receptor antagonists, TIM-1/TIM-4 blocking antibodies
43. 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 fusion1,11.
Possible treatments: ADAM17 inhibitors, metalloprotease inhibitors, TAPI-0, TAPI-1
44. 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 pneumonia11.
Possible treatments: Ezrin peptides
45. 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 approach11.
Possible treatments: LY6E agonists
46. 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 strategy11.
Possible treatments: IFITM3 activators
47. 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 macrophages6.
Possible treatments: anti-CD209 antibodies, mannose analogs, glycodendrimers
48. 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 entry6.
Possible treatments: baricitinib
49. 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)8,18.
Possible treatments: TMEM106B modulators (experimental)
50. 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 subunits8,17,18 .
Possible treatments: etidronate, alendronate
51. 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 levels8.
Possible treatments: Rab7 inhibitors (CID-1067700), vacuolin-1
52. Retromer/retriever/CCC-mediated ACE2 recycling
VPS29/VPS35/VPS35L, SNX27 and CCC (CCDC22/CCDC93/COMMDs) drive retrograde recycling; knockout lowers ACE2 surface and blocks entry8,18,22 .
Possible treatments: retromer stabilizer R55, WASH/Arp2/3 inhibitors (CK-666)
53. Arp2/3-WASH actin branching for endosomal scission
ACTR2/ACTR3/ARPC3/ARPC4 and WASHC4 support retromer budding and receptor recycling required for efficient entry8.
Possible treatments: CK-666, CK-869
54. AP-1 adaptor complex-dependent trafficking
AP1B1/AP1G1 support early (TMPRSS2-biased) entry in airway cells by positioning proviral cargos and routes8.
Possible treatments: brefeldin A, AP-1 inhibitors
55. AHR-ACE2 transcriptional axis modulation
Activated AHR binds ACE2 promoter regions and regulates ACE2, influencing viral attachment/entry; modulating AHR can downshift entry competency in airway epithelium23.
Possible treatments: CH-223191, GNF351, pelargonidin-class AHR modulators
56. 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-endocytosis12.
Possible treatments: pixantrone, heparinase I/II/III, heparin/HS mimetics (e.g., fucoidan, pentosan polysulfate, PG545, necuparanib)
57. 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 route2,12.
Possible treatments: EIPA (amiloride derivative), dynasore, DNM2-K44A, amiloride
58. 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 organelles19.
Possible treatments: PIK-93, enviroxime, bithiazole derivatives, CUR-N399
59. 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 benefits2.
Possible treatments: acrivastine, azelastine, bilastine, desloratadine, diphenhydramine, fexofenadine, loratadine, promethazine, rupatadine, triprolidine
60. 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 immunopathology2.
Possible treatments: chenodeoxycholic acid, ursodeoxycholic acid
61. 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)3.
Possible treatments: camostat, broad-spectrum TTSP inhibitors
62. 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 entry24.
Possible treatments: hzVSF-v13, anti-eVIM monoclonal antibodies
Mechanisms that disrupt the replication or assembly of SARS-CoV-2 within host cells.
Replication inhibition mechanisms targeting viral proteins.
63. RNA-dependent RNA polymerase (RdRp) inhibition
Possible treatments: remdesivir, molnupiravir, azvudine, bemnifosbuvir, deuremidevir, favipiravir, ribavirin, galidesivir, rifampicin, zidovudine, tenofovir, dolutegravir, raltegravir
64. Non-nucleoside RdRp inhibition
Bind to allosteric sites on RdRp to disrupt RNA synthesis25.
Possible treatments: suramin, dasabuvir, PPI-383
65. Main (M) protease (3CLpro) inhibition
Blocking Mpro prevents viral polyprotein cleavage and can minimize Mpro-driven mitochondrial dysfunction1,2,6,9-11,18,26-29 .
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
66. Papain-like protease (PLpro) inhibition
Blocking PLpro activity, which processes viral polyproteins and disrupts host immune response1,2,9,30 .
Possible treatments: GRL-0617, thiopurine analogs, diiodohydroxyquinoline, Scutellaria barbata, disulfiram
67. Nsp13 helicase inhibition
Possible treatments: myricetin, scutellarein, SSYA10-001, bananin, ivermectin
68. Methyltransferase inhibition
Inhibit viral RNA capping by targeting nsp10/nsp16 complex.
Possible treatments: sinefungin, SAM analogs
69. 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 pathogenesis1,2.
Possible treatments: amantadine, rimantadine, hexamethylene amiloride
70. 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 replication2,32-34 .
Possible treatments: ebselen, PJ34, hesperetin, riluzole
71. 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 packaging7,32.
Possible treatments: RNA-binding inhibitors, LLPS disruptors, phase separation modulators, condensate destabilizers
72. Virion assembly disruption
Possible treatments: nitazoxanide, temoporfin, JNJ-9676, CIM-834, verteporfin
73. Nonstructural protein 1 (Nsp1) inhibition
Targeting Nsp1, which suppresses host gene expression by blocking mRNA entry into ribosomes and causing host mRNA degradation18.
Possible treatments: Nsp1-ribosome interaction inhibitors, compounds preventing Nsp1 C-terminal domain activity
74. 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 inhibition7.
Possible treatments: designed peptidomimetics, small molecules stabilizing disorder-to-order transitions
75. 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 function7.
Possible treatments: metal chelators, Cu(II) mimetics, W161/H165-targeting compounds
76. 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
77. 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 formation.
Possible treatments: F2124-0890, ADP-ribose analogs, macrodomain inhibitors, thiopurine analogs, GRL-0617 derivatives, VE-112, VE-157, disulfiram, PLP_CoV2_3k, ebselen
78. 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 synthesis.
Possible treatments: K22, AM580, memantine, enoxacin, cetylpyridinium chloride, hexachlorophene
79. 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
80. Nsp6 autophagy modulation inhibition
Counteracting Nsp6's ability to limit autophagosome expansion, which may help the virus evade autophagy-mediated viral clearance.
Possible treatments: autophagy enhancers specifically targeting Nsp6 mechanisms, compounds restoring normal autophagosome formation
81. Nsp7-Nsp8 primase complex disruption
Targeting the Nsp7-Nsp8 complex that functions as a primase for RdRp, essential for initiating RNA synthesis18.
Possible treatments: small molecules disrupting Nsp7-Nsp8 protein-protein interactions, compounds preventing primase activity
82. 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 immunity18,36.
Possible treatments: suramin derivatives, nucleic acid analogs, small molecules targeting the dimerization interface, DNA-binding inhibitors, quinoline derivatives
83. 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 evasion18,37.
Possible treatments: compounds targeting Nsp10-Nsp14/Nsp16 interfaces, Nsp10 zinc finger inhibitors
84. 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 capping18.
Possible treatments: myricetin, scutellarein, SSYA10-001, triazole derivatives, bismuth salts, vapreotide, 1, 2, 3-triazole derivatives, HE602
85. 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 fidelity1,18,37,38 .
Possible treatments: ribavirin, sinefungin, aurintricarboxylic acid, GRL-0617-like compounds, Y3, suramin, ZINC09432058, tanshinone derivatives, thymoquinone, gossypol, SAM analogs
86. Nsp15 endoribonuclease inhibition
Mechanisms that target the viral endoribonuclease Nsp15, which helps SARS-CoV-2 evade host immune detection18,39.
Possible treatments: acrylamide-based covalent inhibitors
87. 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 replication1,11,18 .
Possible treatments: sinefungin, SAM analogs, 2'-O-methyltransferase inhibitors
88. 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
89. 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 release2.
Possible treatments: emodin, 5-hydroxymethyl-2-furaldehyde, adamantane derivatives, hexamethylene amiloride, potassium channel blockers, calcium channel blockers, diltiazem
90. 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 evasion7.
Possible treatments: small molecules disrupting membrane localization, peptidomimetics, subcellular targeting disruptors
91. 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 storms7.
Possible treatments: TRAF interaction inhibitors, selective NF-κB modulators, NLRP3 pathway disruptors
92. 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
93. 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
94. 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 detection.
Possible treatments: proteasome activators, ER stress modulators, MHC-I stabilizing compounds, IRE1α-targeting drugs, ATF6 pathway modulators
95. ORF9b mitochondrial targeting inhibition
Preventing ORF9b from suppressing host innate immunity through targeting mitochondria and disrupting MAVS signalosome formation, which impairs interferon responses.
Possible treatments: mitochondrial function enhancers, TOM70 interaction inhibitors, DRP1 activators, MAVS pathway stimulators, mitochondrial antiviral compounds
96. ORF10 function inhibition
Blocking the potential roles of ORF10 in viral pathogenesis and replication.
Possible treatments: compounds disrupting ORF10-host protein interactions, CUL2 ubiquitin ligase complex inhibitors
97. 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 analogs37,38.
Possible treatments: VT00180, VT00249, VT00123-R, VT00421, VT00218, bismuth(III) compounds
98. 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 activity37.
Possible treatments: VT00079, VT00123-S, VT00218
99. 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 efficacy37.
Possible treatments: His268-rotamer stabilizers, metal-site-adjacent allosteric binders
100. 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 activity37.
Possible treatments: VT00258, VT00259, nsp10-directed PROTAC warheads
101. 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 coverage18,35.
Possible treatments: JNJ-9676, CIM-834
102. 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 inhibitors27-29.
Possible treatments: Mpro-PROTACs recruiting FBXO22/ZBTB25/Parkin, VHL/CRBN-based degraders
103. 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 cells28.
Possible treatments: cat-MMP14 (soluble catalytic domain), pro-PL-MMP14 (PLpro-activated MMP14 proenzyme)
104. 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 cells25.
Possible treatments: rose bengal, 3-O-acetyl-11-keto-β-boswellic acid (AKBA), theaflavin-3-gallate, dryocrassin ABBA, meclinertant, omaveloxolone
105. 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 catalysis25.
Possible treatments: venetoclax, omaveloxolone, meclinertant, dryocrassin ABBA, BMS-986142
106. 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 assays25.
Possible treatments: lenrispodun, paritaprevir, saikosaponin B2, fenretinide
107. 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 microenvironment18.
Possible treatments: nirmatrelvir, optimized Mpro macrocycles, pore-tethered Mpro inhibitors
108. 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 machinery2.
Possible treatments: elbasvir, ledipasvir, sofosbuvir, velpatasvir
109. 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) domain30.
Possible treatments: engineered ubiquitin variants (UbVs), Ubl-catalytic domain interface disruptors
Targeting Host Proteins/Factors
Replication inhibition mechanisms targeting host proteins/factors.
110. Nucleotide depletion
Inducing viral mutagenesis or depleting nucleotide pools.
Possible treatments: molnupiravir
111. GTP depletion
Inhibition of IMP dehydrogenase depleting guanosine nucleotides2.
Possible treatments: ribavirin, mycophenolate mofetil, azathioprine
112. Pyrimidine depletion
Inhibition of dihydroorotate dehydrogenase depleting pyrimidine nucleotides.
Possible treatments: leflunomide, teriflunomide
113. Deoxyribonucleotide depletion
Inhibition of ribonucleotide reductase reducing deoxyribonucleotide pools.
Possible treatments: hydroxyurea
114. Glucose deprivation
Competitive inhibition of glucose metabolism to limit viral energy sources40.
Possible treatments: 2-deoxy-D-glucose, KAN0438757, 3PO
115. Amino acid depletion
Depletion of asparagine to inhibit viral protein synthesis.
Possible treatments: asparaginase
116. Iron chelation
Sequestration of iron to limit availability for viral replication.
Possible treatments: deferoxamine
117. Methyl donor depletion
Inhibition of S-adenosylmethionine synthesis impairing viral RNA methylation.
Possible treatments: cycloleucine
118. Glutamine antagonism
Inhibition of glutamine metabolism to reduce nucleotide precursors40.
Possible treatments: 6-diazo-5-oxo-L-norleucine
119. 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 cholesterol8.
Possible treatments: simvastatin, atorvastatin, fluvastatin, hydroxypropyl-β-cyclodextrin, 25-hydroxycholesterol
120. 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)41.
Possible treatments: BMS309403, CRE-14
121. 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 infection14.
Possible treatments: GW441756, AG879
122. 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 intervention42.
Possible treatments: roscovitine (seliciclib), flavopiridol, dinaciclib, SNS-032
123. 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 signaling43.
Possible treatments: fasudil, GSK269962A, atorvastatin, Y-27632, NSC23766, ZCL278, simvastatin
124. 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 vitro2,23,27,29,44 .
Possible treatments: romidepsin, vorinostat, entinostat, tazemetostat, BRM/BRG1 inhibitors, valproic acid
125. 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 replication20,45.
Possible treatments: UNC0642, UNC0638, BIX01294, MS1262, UNC1999, tazemetostat, YX59-126
126. 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 coronaviruses.
Possible treatments: thapsigargin, sephin1, TUDCA, 4-phenylbutyrate
127. 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 vivo2.
Possible treatments: metformin, AICAR, berberine, rapamycin, everolimus, sirolimus
128. 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 replication46.
Possible treatments: siRNA-SLBP, antisense-gapmers, SLBP-RBD inhibitors
129. 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 growth46.
Possible treatments: siRNA-FUBP3, RNA-interface disruptors
130. 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-246.
Possible treatments: siRNA-RPL10A/RPS3A/RPS14, ribosomal-PPI modulators
131. 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 enhancement46.
Possible treatments: recombinant SFL, SFL-mRNA therapeutics
132. Mitochondrial bioenergetic preservation
Active SARS-CoV-2 main protease (Mpro) collapses oxidative phosphorylation, depolarises or hyper-polarises mitochondria and fragments their network; stabilising the respiratory chain or blocking Mpro-mediated cleavage of mitochondrial proteins can maintain ATP production and limit virus-induced cell damage6,26,40,47,48 .
Possible treatments: SS-31 peptide, MitoQ, CoQ10, nicotinamide riboside, metformin, resveratrol, TOM70-agonist peptides, macrocyclic ORF9b-TOM70 blockers, VBIT-4, VBIT-12, VDAC1-neutralising antibody, Mdivi-1
133. 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 signaling2,15.
Possible treatments: selumetinib, trametinib, cobimetinib, ATR-002, zapnometinib
134. DYRK1A depletion / degradation
Knocking out or destabilising DYRK1A lowers ACE2/DPP4/ANPEP transcription and blocks double-membrane-vesicle formation, jointly impairing coronavirus entry and early RNA-replication steps15,49.
Possible treatments: DYRK1A-targeting PROTACs, CRISPR/siRNA-DYRK1A, nuclear-export mutants, harmalogs
135. TOM70 functional restoration
Stabilise or up-regulate TOM70 to counteract ORF9b-induced MAVS suppression, prevent lactate over-production and maintain antiviral oxidative phosphorylation47.
Possible treatments: 17-AAG analogues, celastrol derivatives, TOM70-agonist small molecules
136. 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 severity48.
Possible treatments: VBIT-4, VBIT-12, VDAC1-neutralising antibody, metformin, sulindac, hexokinase-mimetic peptides
137. 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 release40.
Possible treatments: KAN0438757, 3PO
138. 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 inflammation40.
Possible treatments: Mdivi-1
139. 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 role27,29,50 .
Possible treatments: SG-inducing eIF2α modulators, halofuginone, pateamine-A analogs, G3BP-stabilising stapled peptides, small-molecule N-G3BP PPI disruptors
140. 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 damage2,28,51 .
Possible treatments: minocycline, doxycycline, tetracycline
141. 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 hamsters2,10.
Possible treatments: sabizabulin, colchicine, vinblastine, vincristine
142. 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 infection1,11.
Possible treatments: SLC6A19 inhibitors, amino acid transport blockers
143. 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 activation1,17.
Possible treatments: cyclosporine A, tacrolimus
144. 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 replication32.
Possible treatments: RNF2 activators, ubiquitin ligase enhancers, RNF2-N protein interaction stabilizers
145. 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 replication32.
Possible treatments: ARL15 activators, GTPase enhancers, ARL15-N protein interaction stabilizers
146. 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 vivo33.
Possible treatments: Neu5Ac2en-OAcOMe (cell-permeable DANA analog), DANA/Neu5Ac2en derivatives with NEU1 selectivity
147. 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 HCoVs8.
Possible treatments: SAR405, PIK-III
148. TMEM41B-dependent autophagosome initiation
Conserved coronavirus dependency; early autophagy membrane remodeling supports replication organelle formation8.
Possible treatments: TMEM41B inhibitors
149. SREBP/SCAP/MBTPS1/2 lipid program
Master regulators of fatty acid/cholesterol synthesis required for coronavirus replication; disruption limits entry/replication8,27.
Possible treatments: fatostatin, betulin, PF-429242
150. Lysosomal cholesterol export (NPC1/NPC2)
NPC1/NPC2 move cholesterol from lumen to membrane; required for CoV entry/fusion and trafficking8.
Possible treatments: U18666A, imipramine, 25-hydroxycholesterol
151. 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 responses2,8.
Possible treatments: fluvoxamine, naltrexone, PB28
152. eEF1A1 translation elongation factor
Host translation factor leveraged by SARS-CoV-2; inhibition shows potent antiviral activity in vitro and in vivo8.
Possible treatments: plitidepsin
153. 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 pathway34.
Possible treatments: dibenzoylmethane, Z-VEID-FMK, caspase-6 inhibitors
154. 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 fibrosis23.
Possible treatments: CH-223191, GNF351, BAY2416964
155. 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 responses23.
Possible treatments: PARP7 inhibitors
156. 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 modifications27.
Possible treatments: TRMT1 inhibitors, RNA-binding aptamers that block TRMT1-tRNA interaction
157. 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 inflammation2,17.
Possible treatments: carfilzomib
158. 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 expansion18.
159. 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 replication18.
Possible treatments: 1, 6-hexanediol-class probes, condensate-modulating chemotypes, nsp-RNA interface inhibitors
160. 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 outcomes18.
Possible treatments: rapamycin, spermidine, ER-phagy activators, nsp3/4 ectodomain interaction blockers
161. 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-219,52.
Possible treatments: ivermectin, lithium, ebselen
162. 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 replication2.
Possible treatments: pyrimethamine
163. 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 responses2.
Possible treatments: vemurafenib
164. 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 assembly2.
Possible treatments: lonafarnib
165. 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 replication2.
Possible treatments: miglustat
166. 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 replication2,53.
Possible treatments: lithium
167. Phosphoinositide 3-kinase (PI3K) inhibition
Blocking the PI3K/AKT/mTOR signaling pathway, which is crucial for cell survival, proliferation, and metabolism, and may be exploited by SARS-CoV-2 to facilitate replication2.
Possible treatments: duvelisib
168. 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 stress2.
Possible treatments: rucaraparib
169. 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 cytokines2.
Possible treatments: entrectinib, nilotinib, vandetanib
170. 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 replication22.
Possible treatments: COMM domain inhibitors, PX domain antagonists, RRM-targeting small molecules
171. 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 production29.
Possible treatments: TRMT1 inhibitors, RNA-binding aptamers that block TRMT1-tRNA interaction
Viral Egress & Budding Inhibition
Mechanisms that prevent or delay release of newly-formed virions from infected cells.
172. 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 spread16,18.
Possible treatments: IFN-β priming, BST2 agonist peptides, small-molecule ORF7a-BST2 interface blockers
173. 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 release18.
Possible treatments: TRPML1 inhibitors, lysosomal exocytosis blockers, PIKfyve-pathway modulators
Host Immune Modulation
Mechanisms that modulate the host immune response to enhance antiviral activity or reduce immunopathology.
174. Cytokine storm suppression
Anti-inflammatory agents target cytokine pathways (IL-1/IL-6/JAK-STAT/TNF-α/complement) or inflammasomes to mitigate excessive inflammation2,5,6,9,17,24,48,53-56 .
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
175. Interferon (type I/II) signaling enhancement
Boosting type I/II interferons or upstream sensors (e.g., STING, RIG-I) to stimulate antiviral gene expression6,27,53 .
Possible treatments: interferon-beta, interferon-alpha, interferon-gamma, nitazoxanide
176. Pegylated interferon-λ receptor agonists
Peg-IFN-λ engages IFNLR1 on respiratory epithelium, amplifies local ISGs with minimal systemic inflammation6,57.
Possible treatments: peginterferon λ-1a, peg-IFN-β-1a
177. Adaptive immune enhancement
Promoting T-cell/B-cell activity or passive antibody transfer to target infected cells6.
Possible treatments: convalescent plasma, monoclonal antibodies, intravenous immunoglobulin (IVIG), thymosin alpha 1, interleukin-7, interleukin-2, nivolumab
178. Innate immune stimulation
Possible treatments: imiquimod, resiquimod, polyinosinic-polycytidylic acid (poly I:C), monophosphoryl lipid A, CpG oligonucleotides, NOD1/2 agonists
179. Zinc supplementation
Potentially interfering with viral replication.
Possible treatments: zinc sulfate, zinc gluconate
180. Selenium supplementation
Enhancing antioxidant defenses and potentially inhibiting viral replication.
Possible treatments: sodium selenite, selenomethionine
181. Micronutrient supplementation for immune system support
Additional vitamins, minerals, and cofactors essential for immune cell function and signaling59.
Possible treatments: vitamin A, vitamin C, vitamin D, vitamin E, vitamin B6, vitamin B12, zinc, selenium, iron, copper, magnesium, vitamin K
182. Immune regulation
Modulating regulatory immune cells (e.g., Tregs) or checkpoint pathways to balance inflammation.
Possible treatments: low-dose interleukin-2, abatacept, sirolimus
183. 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-1960.
Possible treatments: BIBO3304, BIBP3226
184. cGAS-STING agonists
Activating STING to enhance interferon production58.
Possible treatments: DMXAA, 2'3'-cGAMP, ADU-S100, diABZI
185. GM-CSF pathway inhibition
Neutralising granulocyte-macrophage colony-stimulating factor (GM-CSF) or its receptor blunts monocyte/macrophage-driven cytokine storm and lung injury in severe COVID-1958,61.
Possible treatments: mavrilimumab, lenzilumab, otilimab, sargramostim
186. IL-17 axis blockade
Blocking interleukin-17 signaling counters ORF8-mediated IL-17 mimicry and downstream NF-κB activation, reducing neutrophil recruitment and pulmonary damage23,58.
Possible treatments: secukinumab, ixekizumab, brodalumab
187. Mast-cell stabilisation & IgE-axis inhibition
Stabilising mast cells or neutralising free IgE to quell IL-4/IL-13-mediated “IgE storm” that accompanies severe COVID-19 in some variants5.
Possible treatments: omalizumab, cromolyn sodium, ketotifen, rupatadine
188. 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 load59.
Possible treatments: sodium butyrate, tributyrin, propionate pro-drugs
189. 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 inflammation61.
Possible treatments: NIBR-189, GSK 682753A
190. GM-CSF for alveolar-macrophage function
Nebulised rh-GM-CSF re-educates dysregulated lung macrophages, improves gas exchange and promotes viral clearance without provoking cytokine-release syndrome61.
Possible treatments: sargramostim, rh-GM-CSF
191. 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 thrombosis2,15,62 .
Possible treatments: fostamatinib, entospletinib, GS-9973, R406
192. LAIR-1 engagement & STAT1/JAK-STAT suppression
Engaging the inhibitory receptor LAIR-1 with polymerised type I collagen down-regulates STAT-1 phosphorylation, curbs JAK/STAT-driven cytokine output and thereby dampens COVID-19 hyper-inflammation55.
Possible treatments: collagen-PVP (polymerised type I collagen), LAIR-1-agonist peptides, collagen-mimetic hydrogels
193. 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 function40.
Possible treatments: epacadostat, navoximod
194. 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 mice10.
Possible treatments: ibrutinib, zanubrutinib, acalabrutinib, spebrutinib
195. 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 hamsters2,10.
Possible treatments: tradipitant, aprepitant, orvepitant
196. TLR4-spike protein interaction blockade
Spike protein directly binds TLR4 to enhance viral attachment, increase membrane surface virus concentration, and activate downstream inflammatory signaling (IL-1β, IL-6), inducing antibacterial-like immune responses11,63.
Possible treatments: TLR4 antagonists, eritoran, anti-TLR4 antibodies, lipopolysaccharide analogs
197. 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-1933.
Possible treatments: Neu5Ac2en-OAcOMe, other small-molecule NEU1 inhibitors
198. 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 levels6.
Possible treatments: umbilical cord-derived MSCs, bone marrow-derived MSCs, adipose-derived MSCs, menstrual blood-derived MSCs
199. 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 replication6.
Possible treatments: MSC-derived exosomes, engineered exosomes with specific miRNAs
200. 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 trafficking38.
Possible treatments: Tollip C2-domain peptides/mini-proteins, LC3-interaction enhancers, selective Tollip-trafficking modulators
201. 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 hyperinflammation23.
Possible treatments: CH-223191, GNF351, tapinarof, indole-3-carbinol, diindolylmethane
202. 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 responses27.
Possible treatments: protease-resistant TonEBP fragments, small-molecule TonEBP activators
203. 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-192,17.
Possible treatments: imatinib
204. CX3CR1 (fractalkine) signaling modulation
Fractalkine-CX3CR1 drives neuron-microglia crosstalk and pro-inflammatory recruitment; down-modulation reduces microgliosis and cytokine output in neuroinflammation63.
Possible treatments: gabapentin, anti-CX3CR1 monoclonal antibodies, fractalkine-neutralizing biologics, small-molecule CX3CR1 antagonists
205. 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 function2.
Possible treatments: pyridostigmine bromide
206. 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-192.
Possible treatments: dexmedetomidine
207. Macrolide immunomodulation
Utilizing macrolide antibiotics for their secondary immunomodulatory properties, which can dampen excessive inflammatory responses2.
Possible treatments: azithromycin, fidaxomicin
208. 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 infection2.
Possible treatments: timolol maleate
209. 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 signaling29.
Possible treatments: protease-resistant TonEBP-derived peptides, small-molecule TonEBP activators
Microbiome Modulation
Mechanisms that modulate the microbiome to enhance antiviral activity or reduce immunopathology.
210. 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 responses23,59.
Possible treatments: Intranasal Lactobacillus casei spray, Streptococcus salivarius K12 lozenges, Dolosigranulum pigrum lysate drops
Hemostasis & Thrombosis Management
Mechanisms that address coagulopathy and prevent thrombosis, common in severe COVID-19.
211. Anticoagulant therapy
Possible treatments: heparin, enoxaparin, dalteparin, tinzaparin
212. Antiplatelet therapy
Possible treatments: aspirin, clopidogrel, caplacizumab
213. Direct thrombin inhibitors
Inhibit thrombin activity to prevent fibrin formation64.
Possible treatments: dabigatran, argatroban, bivalirudin, lepirudin
214. Direct factor Xa inhibitors
Directly inhibit factor Xa to reduce thrombin generation.
Possible treatments: rivaroxaban, apixaban, edoxaban
215. Indirect factor Xa inhibitors
Enhance antithrombin-mediated inhibition of factor Xa.
Possible treatments: fondaparinux
216. Vitamin K antagonists
Inhibit synthesis of vitamin K-dependent clotting factors.
Possible treatments: warfarin
217. P2Y12 receptor inhibitors
Block ADP-induced platelet activation and aggregation.
Possible treatments: clopidogrel, prasugrel, ticagrelor, ticlopidine
218. Glycoprotein IIb/IIIa inhibitors
Prevent fibrinogen binding and platelet cross-linking.
Possible treatments: abciximab, eptifibatide, tirofiban
219. Phosphodiesterase inhibitors
Increase cAMP levels, reducing platelet activation.
Possible treatments: dipyridamole, cilostazol
220. Protease-activated receptor-1 antagonists
Inhibit thrombin-induced platelet aggregation.
Possible treatments: vorapaxar
221. Fibrinolytic agents
Lyse existing thrombi by converting plasminogen to plasmin64.
Possible treatments: alteplase, tenecteplase, reteplase, streptokinase
222. Antithrombin III supplementation
Supplement antithrombin to enhance anticoagulation.
Possible treatments: antithrombin III concentrate
223. Heparin-like agents
Exert anticoagulant effects similar to heparin.
Possible treatments: danaparoid
224. NSP3-fibrinogen interaction blockade
Agents that obstruct extracellular NSP3 binding to fibrinogen, normalising fibrin formation and mitigating virus-driven hyper-coagulation65,66.
Possible treatments: anti-fibrinogen-site peptides, NSP3 protease inhibitors
225. Platelet FcγRIIa blockade
Monoclonal antibodies or engineered Fc fragments that block IgG engagement of platelet FcγRIIa, preventing afucosylated IgG-driven platelet activation and thrombus formation62.
Possible treatments: anti-FcγRIIa mAb (IV.10), FcγRIIa-Fc chimera, Syk-decoy peptides
226. Serotonin transporter / 5-HT receptor inhibition
SSRIs decrease intraplatelet serotonin; 5-HT₂/5-HT₃ antagonists blunt serotonin-amplified aggregation, collectively reducing COVID-19-associated thrombosis2,62.
Possible treatments: fluvoxamine, sertraline, fluoxetine, vortioxetine, ketanserin, granisetron
227. 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 binding18,64,65,67 .
Possible treatments: recombinant ADAMTS-13, caplacizumab, VWF-neutralising antibodies
228. 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 dysregulation64.
Possible treatments: recombinant TFPI (tifacogin-class), TFPI-mimetics
229. Thrombomodulin (THBD) activation / recombinant thrombomodulin
Enhance the thrombin-thrombomodulin-protein C axis to neutralize prothrombotic signaling while preserving anticoagulant and anti-inflammatory effects64.
Possible treatments: recombinant thrombomodulin (ART-123/thrombomodulin alfa)
230. Protein C pathway restoration (PROC/SERPINC1 axis)
Restore impaired natural anticoagulant circuits noted among CCC hubs (PROC, SERPINC1), aiming to reduce microthrombi and immunothrombosis64.
Possible treatments: protein C concentrate, antithrombin concentrate
231. 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 responses64.
Possible treatments: SERPINA5 replacement/induction (research-stage), STAT1-pathway supportive agents
232. 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 fibrosis64.
Possible treatments: GPRP-analogue fibrin-polymerization blockers, adjunct antifibrotics
233. Prothrombin (F2) level/function normalization
Meta-analysis shows F2 downregulation; careful, context-specific normalization may restore hemostatic balance while avoiding prothrombotic overshoot64.
Possible treatments: prothrombin complex concentrates
234. α2-Antiplasmin (SERPINF2) tuning
As a CCC hub, SERPINF2 (plasmin inhibitor) modulation could re-balance fibrinolysis vs. thrombosis in COVID-associated coagulopathy64.
Possible treatments: plasmin/α2-antiplasmin interface modulators
Inflammation & Oxidative Stress Reduction
Mechanisms that reduce tissue damage caused by inflammation and oxidative stress.
235. 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/TMPRSS221.
Possible treatments: sulforaphane, bardoxolone methyl, dimethyl fumarate, resveratrol, curcumin, oltipraz, PB125, epigallocatechin gallate
236. 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 damage42.
Possible treatments: doxycycline, minocycline, marimastat, batimastat, quercetin, EGCG, SB-3CT
237. COX-2 inhibition
Possible treatments: celecoxib, etoricoxib, meloxicam, boswellic acids, curcumin, GPR4 antagonists, NE-52-QQ57
238. NF-κB inhibition
Inhibition of pro-inflammatory transcription factor NF-κB to reduce cytokine production (TLR2/4 blockers overlap here)63,67,68 .
Possible treatments: parthenolide, curcumin, quercetin, celastrol, sulforaphane
239. ROS scavenging
Neutralizing reactive oxygen species to prevent oxidative damage.
Possible treatments: vitamin C, vitamin E, melatonin, CoQ10, N-acetylcysteine, alpha-lipoic acid
240. Glutathione enhancement
Boosting endogenous glutathione synthesis or regeneration.
Possible treatments: N-acetylcysteine, alpha-lipoic acid, glutathione, sulforaphane
241. 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 approaches27,29.
Possible treatments: VX-765, belnacasan (VX-740)
242. NLRP3 inflammasome inhibition
Possible treatments: MCC950, glyburide, resveratrol, parthenolide, quercetin, luteolin, Harrisonia perforata
243. SOD mimetics
Mimicking superoxide dismutase to neutralize superoxide radicals.
Possible treatments: tempol, MnTBAP
244. 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 injury21.
Possible treatments: hemin, cobalt protoporphyrin, sulforaphane, dimethyl fumarate, resveratrol, curcumin
245. SIRT1 activation
Activating sirtuins to modulate inflammation and oxidative stress pathways.
Possible treatments: resveratrol, NAD+ precursors, nicotinamide riboside
246. PPAR-γ activation
Activating PPAR-γ to suppress pro-inflammatory signaling.
Possible treatments: pioglitazone, rosiglitazone, curcumin
247. 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 processes70.
Possible treatments: ferrostatin-1, liproxstatin-1, deferoxamine, N-acetylcysteine, vitamin E, ebselen, baicalein
248. 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-1971.
Possible treatments: anti-VCL monoclonal antibodies, vinculin-peptide competitors, small-molecule VCL-actin interface disruptors
249. 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-inflammation11,58,63,68 .
Possible treatments: eritoran, resatorvid
250. 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 cascade27,29,61,68 .
Possible treatments: disulfiram, necrosulfonamide, dimethyl fumarate
251. HIF-1α inhibition
Block hypoxia-driven metabolic re-programming that fuels NET formation and cytokine surges in severe COVID-192,47.
Possible treatments: PX-478, digoxin, acriflavine
252. RAGE antagonism
Interrupt AGE/RAGE signaling linked to TNF-α amplification and endothelial dysfunction in advanced disease47.
Possible treatments: azeliragon, FPS-ZM1, alagebrium
253. 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 injury54.
Possible treatments: NE-52-QQ57, imidazopyridine GPR4 antagonist series
254. CXCL10 (IP-10) / CXCR3 axis blockade
Neutralising 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-1956.
Possible treatments: AMG 487, BMS-936557, ipiliximab, NI-0801, elipovimab
255. 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 pathology40.
Possible treatments: EPA, DHA, protectin D1, resolvin D1
256. 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 damage10,38,69 .
Possible treatments: luteolin, SB203580, selumetinib, Harrisonia perforata, losmapimod, SB203580, doramapimod
257. Extracorporeal cytokine adsorption
Physical removal of excessive cytokines from blood using adsorption columns to rapidly reduce cytokine storm severity in critically ill patients6.
Possible treatments: CytoSorb, oXiris, Toraymyxin
258. 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 airflow23.
Possible treatments: CH-223191, GNF351, tapinarof
259. NLRP12 cleavage suppression
3CLpro cleaves NLRP12, a negative regulator of NLRP3, thereby amplifying cytokine production; preserving NLRP12 function may temper hyperinflammation29.
Possible treatments: NLRP12-stabilizing peptides, cleavage-site blockers, small-molecule NLRP12 agonists
260. 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 tissues63.
Possible treatments: crizanlizumab (anti-P-selectin), rivikizumab/anti-PSGL-1 candidates, rivipansel (GMI-1070; selectin antagonist)
261. 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 damage2.
Possible treatments: montelukast
262. Vascular Endothelial Growth Factor (VEGF) inhibition
Blocking VEGF signaling to reduce virus-induced angiogenesis, vascular permeability, and pulmonary edema associated with severe ARDS2.
Possible treatments: bevacizumab, tivozanib
263. 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 hyperinflammation29.
Possible treatments: NLRP12-stabilizing peptides, cleavage-site blockers, small-molecule NLRP12 agonists
264. IL-18 pathway blockade
Neutralize IL-18 or block IL-18R to minimize inflammasome-driven lung inflammation and pyroptosis68.
Possible treatments: tadekinig alfa (IL-18BP), GSK1070806, anti-IL-18R agents
265. NOX4 (NADPH oxidase-4) inhibition
Reduce ROS that prime/activate NLRP3 and amplify IL-1868.
Possible treatments: setanaxib (GKT137831), apocynin, DPI
266. Caspase-1 → IL-18 maturation blockade
Block caspase-1 to curb processing of pro-IL-18/pro-IL-1β and downstream pyroptosis68.
Possible treatments: belnacasan (VX-765), Z-YVAD-FMK
Complement System Regulation
Mechanisms that control excessive complement activation, which contributes to inflammation.
267. Complement pathway inhibition
Blocking complement components to reduce inflammation.
Possible treatments: eculizumab, ravulizumab, coversin, zilucoplan, cemdisiran, tesidolumab
268. C3 inhibition
Inhibition of C3 to prevent downstream complement activation64.
Possible treatments: pegcetacoplan, AMY-101
269. 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)
270. Classical pathway inhibition
Blocking C1 esterase or C1s to suppress classical pathway activation17.
Possible treatments: cinryze, sutimlimab, ruconest
271. C5a signaling blockade
Targeting C5a or its receptor to reduce inflammatory anaphylatoxin effects62.
Possible treatments: vilobelimab, avdoralimab, IFX-1, NOX-D21
272. Alternative pathway inhibition
Inhibiting Factor B to disrupt alternative pathway amplification.
Possible treatments: iptacopan, LNP023
273. Alternative pathway suppression
Blocking Factor D to halt alternative pathway activation.
Possible treatments: danicopan, ACH-4471
274. Lectin pathway inhibition
Targeting MASP-2 to inhibit lectin pathway initiation.
Possible treatments: narsoplimab, OMS721
275. Targeted complement regulation
Fusion protein to inhibit complement at sites of activation.
Possible treatments: TT30
276. Broad-spectrum inhibition
Recombinant soluble complement receptor 1 (sCR1) for multi-pathway suppression.
Possible treatments: TP10
277. C3a signaling blockade
Neutralising C3a or antagonising C3aR diminishes complement-induced platelet activation and microvascular thrombosis62.
Possible treatments: anti-C3a mAb, SB-290157, PMX-53
Apoptosis & Viral Clearance
Mechanisms that promote the elimination of infected cells or viral components.
278. Apoptosis induction
Triggering programmed cell death in infected cells via Bcl-2 inhibition2.
Possible treatments: venetoclax, navitoclax, obatoclax, gossypol, busulfan, carboplatin, cisplatin, ifosfamide, etopophos
279. Extrinsic apoptosis activation
Activating TRAIL death receptors to induce apoptosis in infected cells.
Possible treatments: conatumumab, dulanermin
280. Fas-mediated apoptosis
Stimulating Fas receptors to trigger caspase-dependent cell death.
Possible treatments: APG101, fas_antibody
281. IAP inhibition
Promoting apoptosis by antagonizing inhibitor of apoptosis proteins (IAPs).
Possible treatments: birinapant, LCL161
282. p53 activation
Possible treatments: nutlin-3a, PRIMA-1MET
283. Autophagy stimulation
Enhancing mTOR-independent/AMPK-mediated degradation of viral components.
Possible treatments: rapamycin, everolimus, spermidine, resveratrol, metformin, trehalose
284. Efferocytosis enhancement
Promoting phagocytic clearance of apoptotic cells containing viral material.
Possible treatments: annexin_A1, resolvin_E1, meritastat
285. Immunogenic cell death
Inducing apoptosis with enhanced antigen presentation for immune clearance.
Possible treatments: oxaliplatin, doxorubicin
286. PINK1/Parkin-mediated mitophagy enhancement
Boost clearance of damaged mitochondria via PINK1/Parkin to lower mtROS and downstream inflammatory signaling47.
Possible treatments: urolithin A, nicotinamide riboside, CNX-074
287. 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 virophagy27.
Possible treatments: Tat-LIR mimetic peptides that stabilize LC3-receptor binding, Galectin-8-NDP52 interface enhancers
288. 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 mechanism29.
Possible treatments: p62 cleavage-site blockers, Tat-LIR mimetic peptides that stabilize LC3-receptor binding
Host Nutrient & Factor Modulation
Mechanisms aimed at manipulating the availability or metabolism of host-derived nutrients and factors essential for viral replication or survival.
289. 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 sequelae67.
Possible treatments: Angiotensin-(1-7) peptide, TXA-127, AVE0991, CGEN-856, CGEN-856S
290. Arginine depletion therapy
Pegylated arginase I lowers extracellular arginine, reducing NO-driven hyper-inflammation and starving viral polyamine synthesis pathways implicated in severe COVID-1940.
Possible treatments: PEG-Arg1 (pegylated arginase I)
291. Polyamine synthesis inhibition
Blocking polyamine synthesis pathways that viruses exploit for replication. SARS-CoV-2 requires polyamines for RNA synthesis and protein translation6.
Possible treatments: difluoromethylornithine (DFMO), SAM486A
292. 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 flux17.
Possible treatments: cyanocobalamin
Immune Evasion Countermeasures
Mechanisms that counteract SARS-CoV-2's ability to suppress host immunity.
293. Viral immune modulation inhibition
Blocking viral proteins that suppress host immunity.
294. 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 metabolism47.
Possible treatments: peptidomimetic C-tail competitors, macrocyclic PPI inhibitors, HSP90-TOM70 stapled-peptides
295. Restoring interferon signaling
Countering viral antagonism of STAT1/IRF pathways to reinstate endogenous interferon responses23,27,29,34,38,47 .
Possible treatments: interferon-beta
296. NSP3 deubiquitinase inhibitors
Blocking NSP3's immune evasion via deubiquitinase activity.
297. 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 output66.
Possible treatments: IFIT5-interface mimetics, NSP3 macrodomain blockers
298. ORF6 protein inhibitors
Neutralizing ORF6-mediated interferon suppression47.
299. NSP1 translation inhibition
Preventing NSP1 from blocking host translation.
300. 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 lungs72.
Possible treatments: KYA1797K, IWP-O1, LGK-974, Wnt-C59, NCB-0846, ETC-1922159, Pyrvinium, E7449, iCRT-14, SM04690
301. 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 signaling36.
Possible treatments: let-7b mimics, exosome-loaded let-7b, inhibitors of Nsp9-let-7b binding, TLR7 agonists
302. 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 signaling50.
Possible treatments: macrocyclic PPI inhibitors, N-terminal decoy peptides, groove-filling hetero-bicycles
303. 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 routing38.
Possible treatments: bafilomycin A1, lysosome-trafficking inhibitors, siRNA-TOLLIP, IFNAR1/IFNGR1 endocytosis-blockers
304. 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 signaling38.
Possible treatments: MEK inhibitors (selumetinib, trametinib), p38 inhibitors (losmapimod), IKK/NF-κB pathway inhibitors, N7-MTase inhibitors (sinefungin-class/analogs)
305. 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 growth34.
Possible treatments: dibenzoylmethane, Z-VEID-FMK, caspase-6 inhibitors
306. RLR/NEMO axis preservation from 3CLpro antagonism
3CLpro cleaves RIG-I (Q10), reshapes MAVS (ubiquitination/SUMOylation), and cleaves NEMO (multiple sites), reducing IFN induction27.
Possible treatments: 5'ppp-dsRNA RIG-I agonists, cell-permeable NEMO309-341 decoy peptides, protein-protein interface stabilizers
307. 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 infection53.
308. 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. Therapeutic strategies could aim to protect these components or otherwise restore the pathway's function29.
Possible treatments: 5'ppp-dsRNA RIG-I agonists, cell-permeable NEMO-derived decoy peptides, protein-protein interface stabilizers
Antiviral Peptides
Mechanisms involving peptides that directly inhibit viral activity.
309. Defensins
Antimicrobial peptides with potential antiviral effects.
Possible treatments: Human neutrophil peptide-1 (HNP-1)
310. Fusion inhibitor peptides
Peptides blocking viral fusion with host membranes.
Possible treatments: EK1C4
311. Lactoferrin
Iron-binding protein with antiviral properties.
Possible treatments: bovine lactoferrin
312. Cathelicidin peptides
Antimicrobial peptide disrupting viral envelopes.
Possible treatments: LL-37
313. Hepcidin
Liver-produced peptide with immunomodulatory effects.
Possible treatments: hepcidin-25
314. TAT-based peptides
Cell-penetrating peptides disrupting viral assembly.
Possible treatments: TAT-SARS2
315. 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 cytokines66.
Possible treatments: InSiPS-AVP1, InSiPS-AVP2, InSiPS-AVP3
RNA Interference
Mechanisms that silence viral genes to inhibit replication.
316. siRNA therapy
Small interfering RNAs targeting viral genes.
Possible treatments: siRNA against RdRp
317. siRNA targeting spike
Silencing spike gene to prevent viral entry.
Possible treatments: siRNA-Spike
318. siRNA targeting nucleocapsid
Inhibiting nucleocapsid gene to disrupt virion formation.
Possible treatments: siRNA-N
319. shRNA therapies
Sustained gene silencing via short hairpin RNA.
Possible treatments: shRNA-ORF1ab
320. miRNA mimics
Using microRNAs to target viral RNA degradation.
Possible treatments: miR-23b
321. 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 damage36,73.
Possible treatments: miR-181 mimic, miR-874 mimic, miR-155 mimic, miR-27a mimic, miR-1290 antagonist, miR-576 inhibitor, let-7b mimic
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