COVID-19 treatment: mechanisms of action
COVID-19 involves the interplay of over 200 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 fusion.
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 fusion2.
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 fusion3,4.
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 entry.
Possible treatments: chlorpromazine, thioridazine
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 entry5.
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 state2.
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 RBD2.
Possible treatments: toremifene, cholecalciferol, famprofazone, flupentixol, oxyphenonium, trazodone, linoleic acid
Targeting Host Proteins/Factors
Entry inhibition mechanisms targeting host proteins/factors.
13. TMPRSS2 inhibition
Possible treatments: camostat, nafamostat, bromhexine, gabexate mesylate, N-0385, Scutellaria barbata
14. ACE2 modulation
Possible treatments: lisinopril, losartan, valsartan, enalapril, telmisartan, resveratrol, berberine, estradiol, melatonin, artefenomel, quercetin
15. 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
16. Heparan sulfate mimicry
Compete with heparan sulfate proteoglycans (HSPGs) to disrupt initial viral attachment8.
Possible treatments: heparin, heparan sulfate mimetics, carrageenan, fucoidan, pentosan polysulfate, necuparanib, PG545
17. Cathepsin L inhibition
Possible treatments: teicoplanin, MDL-28170, E-64d (aloxistatin)
18. Integrin targeting
Block integrin receptors - especially α2β1 (ITGA2) and α5β1, αvβ3 - involved in ACE2-independent entry8.
Possible treatments: cilengitide, SB273005, RGD peptide inhibitors, anti-ITGA2 antibodies, obtustatin, dioscin, natalizumab
19. 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 neuroinflammation8,9.
Possible treatments: EG00229, soluble VEGF-A165b, VEGF-A inhibitors, meclizine, siRNA-NRP1
20. Lipid raft disruption
Deplete membrane cholesterol to destabilize lipid raft-dependent entry mechanisms.
Possible treatments: simvastatin, fluvastatin, methyl-β-cyclodextrin, 25-hydroxycholesterol
21. Surfactant inactivation
Disrupt viral envelopes or spike-receptor interactions via surfactant activity.
Possible treatments: poloxamers, chlorhexidine
22. Inhibition of clathrin-mediated endocytosis or endosomal acidification
Inhibit clathrin-mediated endocytosis or endosomal acidification to prevent viral internalization4.
Possible treatments: chloroquine, hydroxychloroquine, dynasore, mitmab, bafilomycin A1, umifenovir
23. Furin inhibition
Possible treatments: decanoyl-RVKR-chloromethylketone, MI-1851, naphthofluorescein
24. 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 replication10,11.
Possible treatments: lapatinib, AG879, CP-724714
25. 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 cells8,12.
Possible treatments: bemcentinib (BGB-324), gilteritinib, cabozantinib, soluble AXL protein, recombinant NTD protein
26. 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 internalisation4,8,12 .
Possible treatments: meplazumab, anti-CD147 peptide decoys
27. 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 route8,12.
Possible treatments: anti-KREMEN1 mAb, anti-ASGR1 mAb, ASGR1-Fc decoys, siRNA-KREMEN1/ASGR1, cocktail antibodies targeting ASK receptors
28. 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 step8,12.
Possible treatments: polyman-26, glycodendrimers, anti-DC-SIGN mAb, griffithsin, cyanovirin-N, mannan, fucoidans, lectin inhibitors
29. 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.
Possible treatments: BLT-1, ITX5061, anti-SR-B1 mAb
30. 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 endocytosis8.
Possible treatments: anti-KIM-1 mAb, KIM-1-competitive peptides, siRNA-KIM1
31. 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 variants.
Possible treatments: apilimod, UNI418, YM-201636, WX8-125
32. 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 strains13.
Possible treatments: UNC0642, UNC0638, BIX01294
33. MET (c-Met/HGFR) receptor inhibition
Blocking MET tyrosine-kinase disrupts coronavirus internalization and early replication steps, capmatinib shows broad anti-CoV activity in vitro11.
Possible treatments: capmatinib, tepotinib, crizotinib
34. 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 cells14.
Possible treatments: PB125, dimethyl fumarate, sulforaphane
35. 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 models7.
Possible treatments: niclosamide, clofazimine, fluoxetine
36. 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.
Possible treatments: anti-TfR antibodies, TfR-competitive peptides, transferrin-derived blocking agents
37. 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 diabetes8.
Possible treatments: sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin
38. 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 infection8.
Possible treatments: myosin inhibitors, blebbistatin, 2, 3-butanedione monoxime
39. 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 efficacy8.
Possible treatments: HA15, kifunensine, GRP78 antagonists
40. 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 reactions8.
Possible treatments: TTYH2 antagonists, chloride channel blockers
41. 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 intervention8.
Possible treatments: PS receptor antagonists, TIM-1/TIM-4 blocking antibodies
42. 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 fusion1,8.
Possible treatments: ADAM17 inhibitors, metalloprotease inhibitors, TAPI-0, TAPI-1
43. 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 pneumonia8.
Possible treatments: Ezrin peptides
44. 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 approach8.
Possible treatments: LY6E agonists
45. 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 strategy8.
Possible treatments: IFITM3 activators
46. 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 macrophages4.
Possible treatments: anti-CD209 antibodies, mannose analogs, glycodendrimers
47. 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 entry4.
Possible treatments: baricitinib
Mechanisms that disrupt the replication or assembly of SARS-CoV-2 within host cells.
Replication inhibition mechanisms targeting viral proteins.
48. RNA-dependent RNA polymerase (RdRp) inhibition
Possible treatments: remdesivir, molnupiravir, azvudine, bemnifosbuvir, deuremidevir, favipiravir, ribavirin, galidesivir
49. Non-nucleoside RdRp inhibition
Bind to allosteric sites on RdRp to disrupt RNA synthesis.
Possible treatments: suramin, dasabuvir, PPI-383
50. Main (M) protease (3CLpro) inhibition
Blocking Mpro prevents viral polyprotein cleavage and can minimize Mpro-driven mitochondrial dysfunction1,4,6-8,15 .
Possible treatments: paxlovid, lopinavir/ritonavir, atilotrelvir, ensitrelvir, ibuzatrelvir, leritrelvir, lufotrelvir, pomotrelvir, xiannuoxin, GC376, rupintrivir, masitinib, narlaprevir, Scutellaria barbata
51. Papain-like protease (PLpro) inhibition
Possible treatments: GRL-0617, thiopurine analogs, diiodohydroxyquinoline, Scutellaria barbata
52. Nsp13 helicase inhibition
Inhibiting the viral helicase enzyme needed to unwind RNA for replication16.
Possible treatments: myricetin, scutellarein, SSYA10-001, bananin, ivermectin
53. Methyltransferase inhibition
Inhibit viral RNA capping by targeting nsp10/nsp16 complex.
Possible treatments: sinefungin, SAM analogs
54. 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.
Possible treatments: amantadine, rimantadine, hexamethylene amiloride
55. 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 replication17,18.
Possible treatments: ebselen, PJ34, hesperetin
56. 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 packaging5,17.
Possible treatments: RNA-binding inhibitors, LLPS disruptors, phase separation modulators, condensate destabilizers
57. Virion assembly disruption
Inhibit assembly of viral structural proteins and RNA into new virions19.
Possible treatments: nitazoxanide, temoporfin, JNJ-9676, CIM-834
58. Nonstructural protein 1 (Nsp1) inhibition
Targeting Nsp1, which suppresses host gene expression by blocking mRNA entry into ribosomes and causing host mRNA degradation.
Possible treatments: Nsp1-ribosome interaction inhibitors, compounds preventing Nsp1 C-terminal domain activity
59. 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 inhibition5.
Possible treatments: designed peptidomimetics, small molecules stabilizing disorder-to-order transitions
60. 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 function5.
Possible treatments: metal chelators, Cu(II) mimetics, W161/H165-targeting compounds
61. 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
62. 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
63. 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
64. 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
65. 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
66. Nsp7-Nsp8 primase complex disruption
Targeting the Nsp7-Nsp8 complex that functions as a primase for RdRp, essential for initiating RNA synthesis.
Possible treatments: small molecules disrupting Nsp7-Nsp8 protein-protein interactions, compounds preventing primase activity
67. 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 immunity20.
Possible treatments: suramin derivatives, nucleic acid analogs, small molecules targeting the dimerization interface, DNA-binding inhibitors, quinoline derivatives
68. 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 evasion21.
Possible treatments: compounds targeting Nsp10-Nsp14/Nsp16 interfaces, Nsp10 zinc finger inhibitors
69. 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 capping.
Possible treatments: myricetin, scutellarein, SSYA10-001, triazole derivatives, bismuth salts, vapreotide, 1, 2, 3-triazole derivatives, HE602
70. 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 fidelity1,21,22 .
Possible treatments: ribavirin, sinefungin, aurintricarboxylic acid, GRL-0617-like compounds, Y3, suramin, ZINC09432058, tanshinone derivatives, thymoquinone, gossypol, SAM analogs
71. Nsp15 endoribonuclease inhibition
Mechanisms that target the viral endoribonuclease Nsp15, which helps SARS-CoV-2 evade host immune detection23.
Possible treatments: acrylamide-based covalent inhibitors
72. 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 replication1,8.
Possible treatments: sinefungin, SAM analogs, 2'-O-methyltransferase inhibitors
73. 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
74. 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 release.
Possible treatments: emodin, 5-hydroxymethyl-2-furaldehyde, adamantane derivatives, hexamethylene amiloride, potassium channel blockers, calcium channel blockers
75. 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 evasion5.
Possible treatments: small molecules disrupting membrane localization, peptidomimetics, subcellular targeting disruptors
76. 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 storms5.
Possible treatments: TRAF interaction inhibitors, selective NF-κB modulators, NLRP3 pathway disruptors
77. 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
78. 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
79. 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
80. 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
81. 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
82. 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 analogs21,22.
Possible treatments: VT00180, VT00249, VT00123-R, VT00421, VT00218, bismuth(III) compounds
83. 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 activity21.
Possible treatments: VT00079, VT00123-S, VT00218
84. 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 efficacy21.
Possible treatments: His268-rotamer stabilizers, metal-site-adjacent allosteric binders
85. 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 activity21.
Possible treatments: VT00258, VT00259, nsp10-directed PROTAC warheads
86. 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 coverage19.
Possible treatments: JNJ-9676, CIM-834
Targeting Host Proteins/Factors
Replication inhibition mechanisms targeting host proteins/factors.
87. Nucleotide depletion
Inducing viral mutagenesis or depleting nucleotide pools.
Possible treatments: molnupiravir
88. GTP depletion
Inhibition of IMP dehydrogenase depleting guanosine nucleotides.
Possible treatments: ribavirin, mycophenolate mofetil
89. Pyrimidine depletion
Inhibition of dihydroorotate dehydrogenase depleting pyrimidine nucleotides.
Possible treatments: leflunomide, teriflunomide
90. Deoxyribonucleotide depletion
Inhibition of ribonucleotide reductase reducing deoxyribonucleotide pools.
Possible treatments: hydroxyurea
91. Glucose deprivation
Competitive inhibition of glucose metabolism to limit viral energy sources24.
Possible treatments: 2-deoxy-D-glucose, KAN0438757, 3PO
92. Amino acid depletion
Depletion of asparagine to inhibit viral protein synthesis.
Possible treatments: asparaginase
93. Iron chelation
Sequestration of iron to limit availability for viral replication.
Possible treatments: deferoxamine
94. Methyl donor depletion
Inhibition of S-adenosylmethionine synthesis impairing viral RNA methylation.
Possible treatments: cycloleucine
95. Glutamine antagonism
Inhibition of glutamine metabolism to reduce nucleotide precursors24.
Possible treatments: 6-diazo-5-oxo-L-norleucine
96. 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 cholesterol.
Possible treatments: simvastatin, atorvastatin, fluvastatin, hydroxypropyl-β-cyclodextrin, 25-hydroxycholesterol
97. 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)25.
Possible treatments: BMS309403, CRE-14
98. 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 infection10.
Possible treatments: GW441756, AG879
99. 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 intervention26.
Possible treatments: roscovitine (seliciclib), flavopiridol, dinaciclib, SNS-032
100. 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 signaling27.
Possible treatments: fasudil, GSK269962A, atorvastatin, Y-27632, NSC23766, ZCL278, simvastatin
101. 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 vitro28.
Possible treatments: romidepsin, vorinostat, entinostat, tazemetostat, BRM/BRG1 inhibitors
102. 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 replication13,29.
Possible treatments: UNC0642, UNC0638, BIX01294, MS1262, UNC1999, tazemetostat, YX59-126
103. ER stress / UPR modulation
Pharmacologic tuning of the unfolded-protein response (BiP/HSPA5 induction, PERK-eIF2α signalling) restores ER homeostasis, curtails viral protein translation and blocks DMV biogenesis across coronaviruses.
Possible treatments: thapsigargin, sephin1, TUDCA, 4-phenylbutyrate
104. 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 vivo.
Possible treatments: metformin, AICAR, berberine, rapamycin
105. 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 replication30.
Possible treatments: siRNA-SLBP, antisense-gapmers, SLBP-RBD inhibitors
106. 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 growth30.
Possible treatments: siRNA-FUBP3, RNA-interface disruptors
107. 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-230.
Possible treatments: siRNA-RPL10A/RPS3A/RPS14, ribosomal-PPI modulators
108. 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 enhancement30.
Possible treatments: recombinant SFL, SFL-mRNA therapeutics
109. 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 damage4,15,24,31,32 .
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
110. 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 signalling11.
Possible treatments: selumetinib, trametinib, cobimetinib, ATR-002, zapnometinib
111. 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 steps11,33.
Possible treatments: DYRK1A-targeting PROTACs, CRISPR/siRNA-DYRK1A, nuclear-export mutants, harmalogs
112. TOM70 functional restoration
Stabilise or up-regulate TOM70 to counteract ORF9b-induced MAVS suppression, prevent lactate over-production and maintain antiviral oxidative phosphorylation31.
Possible treatments: 17-AAG analogues, celastrol derivatives, TOM70-agonist small molecules
113. 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 severity32.
Possible treatments: VBIT-4, VBIT-12, VDAC1-neutralising antibody, metformin, sulindac, hexokinase-mimetic peptides
114. 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 release24.
Possible treatments: KAN0438757, 3PO
115. 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 inflammation24.
Possible treatments: Mdivi-1
116. 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 role34.
Possible treatments: SG-inducing eIF2α modulators, halofuginone, pateamine-A analogs, G3BP-stabilising stapled peptides, small-molecule N-G3BP PPI disruptors
117. 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 damage35.
Possible treatments: minocycline, doxycycline, tetracycline
118. 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 hamsters7.
Possible treatments: sabizabulin, colchicine, vinblastine
119. 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 infection1,8.
Possible treatments: SLC6A19 inhibitors, amino acid transport blockers
120. 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.
Possible treatments: cyclosporine A, tacrolimus
121. 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 replication17.
Possible treatments: RNF2 activators, ubiquitin ligase enhancers, RNF2-N protein interaction stabilizers
122. 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 replication17.
Possible treatments: ARL15 activators, GTPase enhancers, ARL15-N protein interaction stabilizers
123. 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 vivo18.
Possible treatments: Neu5Ac2en-OAcOMe (cell-permeable DANA analog), DANA/Neu5Ac2en derivatives with NEU1 selectivity
Viral Egress & Budding Inhibition
Mechanisms that prevent or delay release of newly-formed virions from infected cells.
124. 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 spread12.
Possible treatments: IFN-β priming, BST2 agonist peptides, small-molecule ORF7a-BST2 interface blockers
Host Immune Modulation
Mechanisms that modulate the host immune response to enhance antiviral activity or reduce immunopathology.
125. Cytokine storm suppression
Anti-inflammatory agents target cytokine pathways (IL-1/IL-6/JAK-STAT/TNF-α/complement) or inflammasomes to mitigate excessive inflammation3,4,6,32,36-38 .
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
126. Interferon (type I/II) signaling enhancement
Boosting type I/II interferons or upstream sensors (e.g., STING, RIG-I) to stimulate antiviral gene expression4.
Possible treatments: interferon-beta, interferon-alpha, interferon-gamma, nitazoxanide
127. Pegylated interferon-λ receptor agonists
Peg-IFN-λ engages IFNLR1 on respiratory epithelium, amplifies local ISGs with minimal systemic inflammation4,39.
Possible treatments: peginterferon λ-1a, peg-IFN-β-1a
128. Adaptive immune enhancement
Promoting T-cell/B-cell activity or passive antibody transfer to target infected cells4.
Possible treatments: convalescent plasma, monoclonal antibodies, intravenous immunoglobulin (IVIG), thymosin alpha 1, interleukin-7, interleukin-2, nivolumab
129. Innate immune stimulation
Possible treatments: imiquimod, resiquimod, polyinosinic-polycytidylic acid (poly I:C), monophosphoryl lipid A, CpG oligonucleotides, NOD1/2 agonists
130. Zinc supplementation
Potentially interfering with viral replication.
Possible treatments: zinc sulfate, zinc gluconate
131. Selenium supplementation
Enhancing antioxidant defenses and potentially inhibiting viral replication.
Possible treatments: sodium selenite, selenomethionine
132. Micronutrient supplementation for immune system support
Additional vitamins, minerals, and cofactors essential for immune cell function and signaling41.
Possible treatments: vitamin A, vitamin C, vitamin D, vitamin E, vitamin B6, vitamin B12, zinc, selenium, iron, copper, magnesium, vitamin K
133. Immune regulation
Modulating regulatory immune cells (e.g., Tregs) or checkpoint pathways to balance inflammation.
Possible treatments: low-dose interleukin-2, abatacept, sirolimus
134. 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-1942.
Possible treatments: BIBO3304, BIBP3226
135. cGAS-STING agonists
Activating STING to enhance interferon production40.
Possible treatments: DMXAA, 2'3'-cGAMP, ADU-S100, diABZI
136. 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-1940,43.
Possible treatments: mavrilimumab, lenzilumab, otilimab, sargramostim
137. IL-17 axis blockade
Blocking interleukin-17 signaling counters ORF8-mediated IL-17 mimicry and downstream NF-κB activation, reducing neutrophil recruitment and pulmonary damage40.
Possible treatments: secukinumab, ixekizumab, brodalumab
138. 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 variants3.
Possible treatments: omalizumab, cromolyn sodium, ketotifen, rupatadine
139. Short-chain fatty-acid supplementation
Exogenous butyrate / propionate / acetate activate GPR43/GPR109A, damp NLRP3 inflammasome, expand T-regs and boost type I IFN signalling, thereby curbing lung injury and viral load41.
Possible treatments: sodium butyrate, tributyrin, propionate pro-drugs
140. GPR183 (EBI-2) antagonism
Blocking the oxysterol-sensing GPCR GPR183 curbs chemotactic recruitment of inflammatory monocytes/macrophages into the airways while sparing early IFN signalling, easing lung inflammation43.
Possible treatments: NIBR-189, GSK 682753A
141. 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 syndrome43.
Possible treatments: sargramostim, rh-GM-CSF
142. 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 thrombosis11,44.
Possible treatments: fostamatinib, entospletinib, GS-9973, R406
143. 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-inflammation37.
Possible treatments: collagen-PVP (polymerised type I collagen), LAIR-1-agonist peptides, collagen-mimetic hydrogels
144. 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 function24.
Possible treatments: epacadostat, navoximod
145. Bruton's tyrosine-kinase (BTK) inhibition
BTK amplifies myeloid NF-κB / NLRP3 signalling; covalent BTK inhibitors curb IL-6 / IL-1β surges and improve survival in SARS-CoV-2-infected mice7.
Possible treatments: ibrutinib, zanubrutinib, acalabrutinib, spebrutinib
146. Neurokinin-1 receptor (NK₁R) antagonism
Substance-P / NK₁R signalling drives pulmonary oedema and cytokine release; NK₁R antagonists restore fluid balance and damp inflammation in infected hamsters7.
Possible treatments: tradipitant, aprepitant, orvepitant
147. 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 responses8.
Possible treatments: TLR4 antagonists, eritoran, anti-TLR4 antibodies, lipopolysaccharide analogs
148. 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-1918.
Possible treatments: Neu5Ac2en-OAcOMe, other small-molecule NEU1 inhibitors
149. 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 levels4.
Possible treatments: umbilical cord-derived MSCs, bone marrow-derived MSCs, adipose-derived MSCs, menstrual blood-derived MSCs
150. 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 replication4.
Possible treatments: MSC-derived exosomes, engineered exosomes with specific miRNAs
151. 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 trafficking22.
Possible treatments: Tollip C2-domain peptides/mini-proteins, LC3-interaction enhancers, selective Tollip-trafficking modulators
Microbiome Modulation
Mechanisms that modulate the microbiome to enhance antiviral activity or reduce immunopathology.
152. 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 responses41.
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.
153. Anticoagulant therapy
Preventing microthrombi formation in severe cases.
Possible treatments: heparin, enoxaparin, dalteparin, tinzaparin
154. Antiplatelet therapy
Reducing platelet aggregation to prevent clots45.
Possible treatments: aspirin, clopidogrel, caplacizumab
155. Direct thrombin inhibitors
Inhibit thrombin activity to prevent fibrin formation.
Possible treatments: dabigatran, argatroban, bivalirudin
156. Direct factor Xa inhibitors
Directly inhibit factor Xa to reduce thrombin generation.
Possible treatments: rivaroxaban, apixaban, edoxaban
157. Indirect factor Xa inhibitors
Enhance antithrombin-mediated inhibition of factor Xa.
Possible treatments: fondaparinux
158. Vitamin K antagonists
Inhibit synthesis of vitamin K-dependent clotting factors.
Possible treatments: warfarin
159. P2Y12 receptor inhibitors
Block ADP-induced platelet activation and aggregation.
Possible treatments: clopidogrel, prasugrel, ticagrelor, ticlopidine
160. Glycoprotein IIb/IIIa inhibitors
Prevent fibrinogen binding and platelet cross-linking.
Possible treatments: abciximab, eptifibatide, tirofiban
161. Phosphodiesterase inhibitors
Increase cAMP levels, reducing platelet activation.
Possible treatments: dipyridamole, cilostazol
162. Protease-activated receptor-1 antagonists
Inhibit thrombin-induced platelet aggregation.
Possible treatments: vorapaxar
163. Fibrinolytic agents
Lyse existing thrombi by converting plasminogen to plasmin.
Possible treatments: alteplase, tenecteplase, reteplase, streptokinase
164. Antithrombin III supplementation
Supplement antithrombin to enhance anticoagulation.
Possible treatments: antithrombin III concentrate
165. Heparin-like agents
Exert anticoagulant effects similar to heparin.
Possible treatments: danaparoid
166. NSP3-fibrinogen interaction blockade
Agents that obstruct extracellular NSP3 binding to fibrinogen, normalising fibrin formation and mitigating virus-driven hyper-coagulation45,46.
Possible treatments: anti-fibrinogen-site peptides, NSP3 protease inhibitors
167. Platelet FcγRIIa blockade
Monoclonal antibodies or engineered Fc fragments that block IgG engagement of platelet FcγRIIa, preventing afucosylated IgG-driven platelet activation and thrombus formation44.
Possible treatments: anti-FcγRIIa mAb (IV.10), FcγRIIa-Fc chimera, Syk-decoy peptides
168. Serotonin transporter / 5-HT receptor inhibition
SSRIs decrease intraplatelet serotonin; 5-HT₂/5-HT₃ antagonists blunt serotonin-amplified aggregation, collectively reducing COVID-19-associated thrombosis44.
Possible treatments: fluvoxamine, sertraline, fluoxetine, vortioxetine, ketanserin, granisetron
169. 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 binding45,47.
Possible treatments: recombinant ADAMTS-13, caplacizumab, VWF-neutralising antibodies
Inflammation & Oxidative Stress Reduction
Mechanisms that reduce tissue damage caused by inflammation and oxidative stress.
170. 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/TMPRSS214.
Possible treatments: sulforaphane, bardoxolone methyl, dimethyl fumarate, resveratrol, curcumin, oltipraz, PB125, epigallocatechin gallate
171. 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 damage26.
Possible treatments: doxycycline, minocycline, marimastat, batimastat, quercetin, EGCG, SB-3CT
172. COX-2 inhibition
Suppressing prostaglandin-mediated inflammation36.
Possible treatments: celecoxib, etoricoxib, meloxicam, boswellic acids, curcumin, GPR4 antagonists, NE-52-QQ57
173. NF-κB inhibition
Inhibition of pro-inflammatory transcription factor NF-κB to reduce cytokine production (TLR2/4 blockers overlap here)47.
Possible treatments: parthenolide, curcumin, quercetin, celastrol, sulforaphane
174. ROS scavenging
Neutralizing reactive oxygen species to prevent oxidative damage.
Possible treatments: vitamin C, vitamin E, melatonin, CoQ10, N-acetylcysteine, alpha-lipoic acid
175. Glutathione enhancement
Boosting endogenous glutathione synthesis or regeneration.
Possible treatments: N-acetylcysteine, alpha-lipoic acid, glutathione, sulforaphane
176. 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 approaches.
Possible treatments: VX-765, belnacasan (VX-740)
177. NLRP3 inflammasome inhibition
Possible treatments: MCC950, glyburide, resveratrol, parthenolide, quercetin, luteolin, Harrisonia perforata
178. SOD mimetics
Mimicking superoxide dismutase to neutralize superoxide radicals.
Possible treatments: tempol, MnTBAP
179. 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 injury14.
Possible treatments: hemin, cobalt protoporphyrin, sulforaphane, dimethyl fumarate, resveratrol, curcumin
180. SIRT1 activation
Activating sirtuins to modulate inflammation and oxidative stress pathways.
Possible treatments: resveratrol, NAD+ precursors, nicotinamide riboside
181. PPAR-γ activation
Activating PPAR-γ to suppress pro-inflammatory signaling.
Possible treatments: pioglitazone, rosiglitazone, curcumin
182. 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 processes49.
Possible treatments: ferrostatin-1, liproxstatin-1, deferoxamine, N-acetylcysteine, vitamin E, ebselen, baicalein
183. 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-1950.
Possible treatments: anti-VCL monoclonal antibodies, vinculin-peptide competitors, small-molecule VCL-actin interface disruptors
184. 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-inflammation8,40.
Possible treatments: eritoran, resatorvid
185. 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 cascade43.
Possible treatments: disulfiram, necrosulfonamide, dimethyl fumarate
186. HIF-1α inhibition
Block hypoxia-driven metabolic re-programming that fuels NET formation and cytokine surges in severe COVID-1931.
Possible treatments: PX-478, digoxin, acriflavine
187. RAGE antagonism
Interrupt AGE/RAGE signalling linked to TNF-α amplification and endothelial dysfunction in advanced disease31.
Possible treatments: azeliragon, FPS-ZM1, alagebrium
188. 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 injury36.
Possible treatments: NE-52-QQ57, imidazopyridine GPR4 antagonist series
189. 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-1938.
Possible treatments: AMG 487, BMS-936557, ipiliximab, NI-0801, elipovimab
190. 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 pathology24.
Possible treatments: EPA, DHA, protectin D1, resolvin D1
191. 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 damage7,22,48 .
Possible treatments: luteolin, SB203580, selumetinib, Harrisonia perforata, losmapimod, SB203580, doramapimod
192. Extracorporeal cytokine adsorption
Physical removal of excessive cytokines from blood using adsorption columns to rapidly reduce cytokine storm severity in critically ill patients4.
Possible treatments: CytoSorb, oXiris, Toraymyxin
Complement System Regulation
Mechanisms that control excessive complement activation, which contributes to inflammation.
193. Complement pathway inhibition
Blocking complement components to reduce inflammation.
Possible treatments: eculizumab, ravulizumab, coversin, zilucoplan, cemdisiran, tesidolumab
194. C3 inhibition
Inhibition of C3 to prevent downstream complement activation.
Possible treatments: pegcetacoplan, AMY-101
195. 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)
196. Classical pathway inhibition
Blocking C1 esterase or C1s to suppress classical pathway activation.
Possible treatments: cinryze, sutimlimab, ruconest
197. C5a signaling blockade
Targeting C5a or its receptor to reduce inflammatory anaphylatoxin effects44.
Possible treatments: vilobelimab, avdoralimab, IFX-1, NOX-D21
198. Alternative pathway inhibition
Inhibiting Factor B to disrupt alternative pathway amplification.
Possible treatments: iptacopan, LNP023
199. Alternative pathway suppression
Blocking Factor D to halt alternative pathway activation.
Possible treatments: danicopan, ACH-4471
200. Lectin pathway inhibition
Targeting MASP-2 to inhibit lectin pathway initiation.
Possible treatments: narsoplimab, OMS721
201. Targeted complement regulation
Fusion protein to inhibit complement at sites of activation.
Possible treatments: TT30
202. Broad-spectrum inhibition
Recombinant soluble complement receptor 1 (sCR1) for multi-pathway suppression.
Possible treatments: TP10
203. C3a signalling blockade
Neutralising C3a or antagonising C3aR diminishes complement-induced platelet activation and microvascular thrombosis44.
Possible treatments: anti-C3a mAb, SB-290157, PMX-53
Apoptosis & Viral Clearance
Mechanisms that promote the elimination of infected cells or viral components.
204. Apoptosis induction
Triggering programmed cell death in infected cells via Bcl-2 inhibition.
Possible treatments: venetoclax, navitoclax, obatoclax, gossypol
205. Extrinsic apoptosis activation
Activating TRAIL death receptors to induce apoptosis in infected cells.
Possible treatments: conatumumab, dulanermin
206. Fas-mediated apoptosis
Stimulating Fas receptors to trigger caspase-dependent cell death.
Possible treatments: APG101, fas_antibody
207. IAP inhibition
Promoting apoptosis by antagonizing inhibitor of apoptosis proteins (IAPs).
Possible treatments: birinapant, LCL161
208. p53 activation
Restoring p53 activity to induce apoptosis in infected cells.
Possible treatments: nutlin-3a, PRIMA-1MET
209. Autophagy stimulation
Enhancing mTOR-independent/AMPK-mediated degradation of viral components.
Possible treatments: rapamycin, everolimus, spermidine, resveratrol, metformin, trehalose
210. Efferocytosis enhancement
Promoting phagocytic clearance of apoptotic cells containing viral material.
Possible treatments: annexin_A1, resolvin_E1, meritastat
211. Immunogenic cell death
Inducing apoptosis with enhanced antigen presentation for immune clearance.
Possible treatments: oxaliplatin, doxorubicin
212. PINK1/Parkin-mediated mitophagy enhancement
Boost clearance of damaged mitochondria via PINK1/Parkin to lower mtROS and downstream inflammatory signalling31.
Possible treatments: urolithin A, nicotinamide riboside, CNX-074
Host Nutrient & Factor Modulation
Mechanisms aimed at manipulating the availability or metabolism of host-derived nutrients and factors essential for viral replication or survival.
213. 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 sequelae47.
Possible treatments: Angiotensin-(1-7) peptide, TXA-127, AVE0991, CGEN-856, CGEN-856S
214. Arginine depletion therapy
Pegylated arginase I lowers extracellular arginine, reducing NO-driven hyper-inflammation and starving viral polyamine synthesis pathways implicated in severe COVID-1924.
Possible treatments: PEG-Arg1 (pegylated arginase I)
215. Polyamine synthesis inhibition
Blocking polyamine synthesis pathways that viruses exploit for replication. SARS-CoV-2 requires polyamines for RNA synthesis and protein translation4.
Possible treatments: difluoromethylornithine (DFMO), SAM486A
Immune Evasion Countermeasures
Mechanisms that counteract SARS-CoV-2's ability to suppress host immunity.
216. Viral immune modulation inhibition
Blocking viral proteins that suppress host immunity.
217. ORF9b-TOM70 interface blockade
Disrupt ORF9b binding to the C-terminus of TOM70 to restore HSP90-mediated MAVS signalling, type-I interferon output and balanced mitochondrial metabolism31.
Possible treatments: peptidomimetic C-tail competitors, macrocyclic PPI inhibitors, HSP90-TOM70 stapled-peptides
218. Restoring interferon signaling
Countering viral antagonism of STAT1/IRF pathways to reinstate endogenous interferon responses22,31.
Possible treatments: interferon-beta
219. NSP3 deubiquitinase inhibitors
Blocking NSP3's immune evasion via deubiquitinase activity.
220. NSP3-IFIT5/ISG15 axis disruption
Small molecules or peptides that block NSP3-mediated de-ISGylation of IFIT5, restoring ISG15-dependent IRF3/NF-κB signalling and type I-IFN output46.
Possible treatments: IFIT5-interface mimetics, NSP3 macrodomain blockers
221. ORF6 protein inhibitors
Neutralizing ORF6-mediated interferon suppression31.
222. NSP1 translation inhibition
Preventing NSP1 from blocking host translation.
223. 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 lungs51.
Possible treatments: KYA1797K, IWP-O1, LGK-974, Wnt-C59, NCB-0846, ETC-1922159, Pyrvinium, E7449, iCRT-14, SM04690
224. 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 signalling20.
Possible treatments: let-7b mimics, exosome-loaded let-7b, inhibitors of Nsp9-let-7b binding, TLR7 agonists
225. 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 signalling34.
Possible treatments: macrocyclic PPI inhibitors, N-terminal decoy peptides, groove-filling hetero-bicycles
226. 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 routing22.
Possible treatments: bafilomycin A1, lysosome-trafficking inhibitors, siRNA-TOLLIP, IFNAR1/IFNGR1 endocytosis-blockers
227. 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 signaling22.
Possible treatments: MEK inhibitors (selumetinib, trametinib), p38 inhibitors (losmapimod), IKK/NF-κB pathway inhibitors, N7-MTase inhibitors (sinefungin-class/analogs)
Antiviral Peptides
Mechanisms involving peptides that directly inhibit viral activity.
228. Defensins
Antimicrobial peptides with potential antiviral effects.
Possible treatments: Human neutrophil peptide-1 (HNP-1)
229. Fusion inhibitor peptides
Peptides blocking viral fusion with host membranes.
Possible treatments: EK1C4
230. Lactoferrin
Iron-binding protein with antiviral properties.
Possible treatments: bovine lactoferrin
231. Cathelicidin peptides
Antimicrobial peptide disrupting viral envelopes.
Possible treatments: LL-37
232. Hepcidin
Liver-produced peptide with immunomodulatory effects.
Possible treatments: hepcidin-25
233. TAT-based peptides
Cell-penetrating peptides disrupting viral assembly.
Possible treatments: TAT-SARS2
234. 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 cytokines46.
Possible treatments: InSiPS-AVP1, InSiPS-AVP2, InSiPS-AVP3
RNA Interference
Mechanisms that silence viral genes to inhibit replication.
235. siRNA therapy
Small interfering RNAs targeting viral genes.
Possible treatments: siRNA against RdRp
236. siRNA targeting spike
Silencing spike gene to prevent viral entry.
Possible treatments: siRNA-Spike
237. siRNA targeting nucleocapsid
Inhibiting nucleocapsid gene to disrupt virion formation.
Possible treatments: siRNA-N
238. shRNA therapies
Sustained gene silencing via short hairpin RNA.
Possible treatments: shRNA-ORF1ab
239. miRNA mimics
Using microRNAs to target viral RNA degradation.
Possible treatments: miR-23b
240. 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 damage20,52.
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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