COVID-19 treatment: mechanisms of action
COVID-19 involves the interplay of over 100 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 cells.
Possible treatments: bamlanivimab, casirivimab/imdevimab, tixagevimab/cilgavimab, regdanvimab, etesevimab, APN01, STI-4398, griffithsin, cyanovirin-N
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 fusion.
Possible treatments: designed peptides mimicking stabilizing mutations
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 fusion1.
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 entry2.
Possible treatments: disorder stabilizers, conformation-selective binders, fusion-incompetent state stabilizers
Targeting Host Proteins/Factors
Entry inhibition mechanisms targeting host proteins/factors.
11. TMPRSS2 inhibition
Block host protease TMPRSS2 to prevent spike priming for membrane fusion.
Possible treatments: camostat, nafamostat, bromhexine, gabexate mesylate, N-0385
12. ACE2 modulation
Modulate ACE2 receptor expression, shedding, or availability to reduce viral docking1.
Possible treatments: lisinopril, losartan, valsartan, enalapril, telmisartan, resveratrol, berberine, estradiol, melatonin, artefenomel, quercetin
13. 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
14. Heparan sulfate mimicry
Compete with heparan sulfate proteoglycans (HSPGs) to disrupt initial viral attachment.
Possible treatments: heparin, heparan sulfate mimetics, carrageenan, fucoidan, pentosan polysulfate, necuparanib, PG545
15. Cathepsin L block
Inhibit endosomal protease cathepsin L (alternative pathway for spike activation).
Possible treatments: teicoplanin, MDL-28170, E-64d (aloxistatin)
16. Integrin targeting
Block integrin receptors - especially α2β1 (ITGA2) and α5β1, αvβ3 - involved in ACE2-independent entry.
Possible treatments: cilengitide, SB273005, RGD peptide inhibitors, anti-ITGA2 antibodies, obtustatin, dioscin
17. 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 neuroinflammation3.
Possible treatments: EG00229, soluble VEGF-A165b, VEGF-A inhibitors, meclizine, siRNA-NRP1
18. Lipid raft disruption
Deplete membrane cholesterol to destabilize lipid raft-dependent entry mechanisms.
Possible treatments: simvastatin, fluvastatin, methyl-β-cyclodextrin, 25-hydroxycholesterol
19. Surfactant inactivation
Disrupt viral envelopes or spike-receptor interactions via surfactant activity.
Possible treatments: poloxamers, chlorhexidine
20. Endocytosis/acidification block
Inhibit clathrin-mediated endocytosis or endosomal acidification to prevent viral internalization.
Possible treatments: chloroquine, hydroxychloroquine, dynasore, mitmab, bafilomycin A1, umifenovir
21. Furin inhibition
Block furin-mediated cleavage of the spike protein to impair viral entry.
Possible treatments: decanoyl-RVKR-chloromethylketone, MI-1851, naphthofluorescein
22. 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 replication4.
Possible treatments: lapatinib, AG879, CP-724714
23. 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 cells5.
Possible treatments: bemcentinib (BGB-324), gilteritinib, cabozantinib
24. 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 internalisation5.
Possible treatments: meplazumab, anti-CD147 peptide decoys
25. 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 route5.
Possible treatments: anti-KREMEN1 mAb, ASGR1-Fc decoys, siRNA-KREMEN1/ASGR1
26. 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 step5.
Possible treatments: polyman-26, glycodendrimers, anti-DC-SIGN mAb, griffithsin, cyanovirin-N
27. 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 infection.
Possible treatments: BLT-1, ITX5061, anti-SR-B1 mAb
28. KIM1/TIM1 antagonism
Kidney-injury molecule-1 serves as an ACE2-independent receptor in tubular epithelia; blocking peptides or monoclonal antibodies may curb renal SARS-CoV-2 infection.
Possible treatments: anti-KIM1 mAb, KIM1-competitive peptides, siRNA-KIM1
29. 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
Mechanisms that disrupt the replication or assembly of SARS-CoV-2 within host cells.
Replication inhibition mechanisms targeting viral proteins.
30. RNA-dependent RNA polymerase (RdRp) inhibition
Nucleoside analogs interfere with viral RNA synthesis.
Possible treatments: remdesivir, molnupiravir, azvudine, bemnifosbuvir, deuremidevir, favipiravir, ribavirin, galidesivir
31. Non-nucleoside RdRp inhibition
Bind to allosteric sites on RdRp to disrupt RNA synthesis.
Possible treatments: suramin, dasabuvir, PPI-383
32. Main (M) protease (3CLpro) inhibition
Blocking viral proteases required for polyprotein cleavage.
Possible treatments: paxlovid, lopinavir/ritonavir, atilotrelvir, ensitrelvir, ibuzatrelvir, leritrelvir, lufotrelvir, pomotrelvir, xiannuoxin, GC376, rupintrivir, masitinib, narlaprevir
33. Papain-like protease (PLpro) inhibition
Blocking PLpro activity, which processes viral polyproteins and disrupts host immune response.
Possible treatments: GRL-0617, thiopurine analogs, diiodohydroxyquinoline
34. Nsp13 helicase inhibition
Inhibiting the viral helicase enzyme needed to unwind RNA for replication6.
Possible treatments: myricetin, scutellarein, SSYA10-001, bananin, ivermectin
35. Methyltransferase inhibition
Inhibit viral RNA capping by targeting nsp10/nsp16 complex.
Possible treatments: sinefungin, SAM analogs
36. Ion channel (E protein) blockade
Disrupting the SARS-CoV-2 envelope (E) protein function.
Possible treatments: amantadine, rimantadine, hexamethylene amiloride
37. Nucleocapsid (N) protein inhibition
Disrupt N protein's RNA binding and oligomerization, preventing viral genome packaging.
Possible treatments: ebselen, PJ34, hesperetin
38. Nucleocapsid protein 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 packaging2.
Possible treatments: RNA-binding inhibitors, LLPS disruptors, phase separation modulators, condensate destabilizers
39. Virion assembly disruption
Inhibit assembly of viral structural proteins and RNA into new virions.
Possible treatments: nitazoxanide, temoporfin
40. 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
41. 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 inhibition2.
Possible treatments: designed peptidomimetics, small molecules stabilizing disorder-to-order transitions
42. 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 function2.
Possible treatments: metal chelators, Cu(II) mimetics, W161/H165-targeting compounds
43. 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
44. 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
45. 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
46. 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
47. 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
48. 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
49. 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.
Possible treatments: suramin derivatives, nucleic acid analogs, small molecules targeting the dimerization interface, DNA-binding inhibitors, quinoline derivatives
50. 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 evasion.
Possible treatments: compounds targeting Nsp10-Nsp14/Nsp16 interfaces, Nsp10 zinc finger inhibitors
51. 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
52. 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 fidelity.
Possible treatments: ribavirin, sinefungin, aurintricarboxylic acid, GRL-0617-like compounds, Y3, suramin, ZINC09432058, tanshinone derivatives, thymoquinone, gossypol, SAM analogs
53. Nsp15 endoribonuclease inhibition
Mechanisms that target the viral endoribonuclease Nsp15, which helps SARS-CoV-2 evade host immune detection7.
Possible treatments: acrylamide-based covalent inhibitors
54. 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
55. 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
56. 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 evasion2.
Possible treatments: small molecules disrupting membrane localization, peptidomimetics, subcellular targeting disruptors
57. 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 storms2.
Possible treatments: TRAF interaction inhibitors, selective NF-κB modulators, NLRP3 pathway disruptors
58. 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
59. 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
60. 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
61. 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
62. 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
Targeting Host Proteins/Factors
Replication inhibition mechanisms targeting host proteins/factors.
63. Nucleotide depletion
Inducing viral mutagenesis or depleting nucleotide pools.
Possible treatments: molnupiravir
64. GTP depletion
Inhibition of IMP dehydrogenase depleting guanosine nucleotides.
Possible treatments: ribavirin, mycophenolate mofetil
65. Pyrimidine depletion
Inhibition of dihydroorotate dehydrogenase depleting pyrimidine nucleotides.
Possible treatments: leflunomide, teriflunomide
66. Deoxyribonucleotide depletion
Inhibition of ribonucleotide reductase reducing deoxyribonucleotide pools.
Possible treatments: hydroxyurea
67. Glucose deprivation
Competitive inhibition of glucose metabolism to limit viral energy sources.
Possible treatments: 2-deoxy-D-glucose
68. Amino acid depletion
Depletion of asparagine to inhibit viral protein synthesis.
Possible treatments: asparaginase
69. Iron chelation
Sequestration of iron to limit availability for viral replication.
Possible treatments: deferoxamine
70. Methyl donor depletion
Inhibition of S-adenosylmethionine synthesis impairing viral RNA methylation.
Possible treatments: cycloleucine
71. Glutamine antagonism
Inhibition of glutamine metabolism to reduce nucleotide precursors.
Possible treatments: 6-diazo-5-oxo-L-norleucine
72. 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
73. 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)8.
Possible treatments: BMS309403, CRE-14
74. 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 infection4.
Possible treatments: GW441756, AG879
75. 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 intervention9.
Possible treatments: roscovitine (seliciclib), flavopiridol, dinaciclib, SNS-032
76. 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 signaling10.
Possible treatments: fasudil, GSK269962A, atorvastatin, Y-27632, NSC23766, ZCL278, simvastatin
77. 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 vitro11.
Possible treatments: romidepsin, vorinostat, entinostat, tazemetostat, BRM/BRG1 inhibitors
78. G9a-m6A-mediated host translational control
Inhibition of the host chromatin-modifying enzyme G9a blocks SARS-CoV-2-induced rewiring of the host m6A epitranscriptome via METTL3, reducing translation, phosphorylation, and secretion of viral and proviral proteins. This disrupts replication and mitigates cytokine-driven immunopathology, lymphopenia, and fibrotic signaling. G9a/EZH2 inhibition reverses SARS-CoV-2-induced upregulation of proteins involved in viral entry (e.g., ACE2), inflammation, angiogenesis, and coagulation, with therapeutic potential against both acute infection and long COVID12.
Possible treatments: UNC0642, MS1262, UNC1999, tazemetostat, YX59-126
79. 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
80. 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
Viral Egress & Budding Inhibition
Mechanisms that prevent or delay release of newly-formed virions from infected cells.
81. 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 spread5.
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.
82. Cytokine storm suppression
Anti-inflammatory agents target cytokine pathways (IL-1/IL-6/JAK-STAT/TNF-α/complement) or inflammasomes to mitigate excessive inflammation1.
Possible treatments: dexamethasone, methylprednisolone, tocilizumab, sarilumab, baricitinib, ruxolitinib, anakinra, canakinumab, infliximab, adalimumab, colchicine, lenzilumab, eculizumab
83. Interferon (type I/II) signaling enhancement
Boosting type I/II interferons or upstream sensors (e.g., STING, RIG-I) to stimulate antiviral gene expression.
Possible treatments: interferon-beta, interferon-alpha, interferon-gamma, nitazoxanide
84. Pegylated interferon-λ receptor agonists
Peg-IFN-λ engages IFNLR1 on respiratory epithelium, amplifies local ISGs with minimal systemic inflammation13.
Possible treatments: peginterferon λ-1a, peg-IFN-β-1a
85. Adaptive immune enhancement
Promoting T-cell/B-cell activity or passive antibody transfer to target infected cells.
Possible treatments: convalescent plasma, monoclonal antibodies, intravenous immunoglobulin (IVIG), thymosin alpha 1, interleukin-7, interleukin-2, nivolumab
86. Innate immune stimulation
Activating innate immunity via PRRs (TLRs, RIG-I, STING) or antiviral effector mechanisms14.
Possible treatments: imiquimod, resiquimod, polyinosinic-polycytidylic acid (poly I:C), monophosphoryl lipid A, CpG oligonucleotides, NOD1/2 agonists
87. Zinc supplementation
Potentially interfering with viral replication.
Possible treatments: zinc sulfate, zinc gluconate
88. Selenium supplementation
Enhancing antioxidant defenses and potentially inhibiting viral replication.
Possible treatments: sodium selenite, selenomethionine
89. Micronutrient supplementation for immune system support
Additional vitamins, minerals, and cofactors essential for immune cell function and signaling15.
Possible treatments: vitamin A, vitamin C, vitamin D, vitamin E, vitamin B6, vitamin B12, zinc, selenium, iron, copper, magnesium, vitamin K
90. Immune regulation
Modulating regulatory immune cells (e.g., Tregs) or checkpoint pathways to balance inflammation.
Possible treatments: low-dose interleukin-2, abatacept, sirolimus
91. 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-1916.
Possible treatments: BIBO3304, BIBP3226
92. cGAS-STING agonists
Activating STING to enhance interferon production14.
Possible treatments: DMXAA, 2'3'-cGAMP, ADU-S100, diABZI
93. 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-1914.
Possible treatments: mavrilimumab, lenzilumab, otilimab
94. IL-17 axis blockade
Blocking interleukin-17 signaling counters ORF8-mediated IL-17 mimicry and downstream NF-κB activation, reducing neutrophil recruitment and pulmonary damage14.
Possible treatments: secukinumab, ixekizumab, brodalumab
95. 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 variants1.
Possible treatments: omalizumab, cromolyn sodium, ketotifen, rupatadine
96. 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 load15.
Possible treatments: sodium butyrate, tributyrin, propionate pro-drugs
Microbiome Modulation
Mechanisms that modulate the microbiome to enhance antiviral activity or reduce immunopathology.
97. 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 responses15.
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.
98. Anticoagulant therapy
Preventing microthrombi formation in severe cases.
Possible treatments: heparin, enoxaparin, dalteparin, tinzaparin
99. Antiplatelet therapy
Reducing platelet aggregation to prevent clots.
Possible treatments: aspirin, clopidogrel
100. Direct thrombin inhibitors
Inhibit thrombin activity to prevent fibrin formation.
Possible treatments: dabigatran, argatroban, bivalirudin
101. Direct factor Xa inhibitors
Directly inhibit factor Xa to reduce thrombin generation.
Possible treatments: rivaroxaban, apixaban, edoxaban
102. Indirect factor Xa inhibitors
Enhance antithrombin-mediated inhibition of factor Xa.
Possible treatments: fondaparinux
103. Vitamin K antagonists
Inhibit synthesis of vitamin K-dependent clotting factors.
Possible treatments: warfarin
104. P2Y12 receptor inhibitors
Block ADP-induced platelet activation and aggregation.
Possible treatments: clopidogrel, prasugrel, ticagrelor, ticlopidine
105. Glycoprotein IIb/IIIa inhibitors
Prevent fibrinogen binding and platelet cross-linking.
Possible treatments: abciximab, eptifibatide, tirofiban
106. Phosphodiesterase inhibitors
Increase cAMP levels, reducing platelet activation.
Possible treatments: dipyridamole, cilostazol
107. Protease-activated receptor-1 antagonists
Inhibit thrombin-induced platelet aggregation.
Possible treatments: vorapaxar
108. Fibrinolytic agents
Lyse existing thrombi by converting plasminogen to plasmin.
Possible treatments: alteplase, tenecteplase, reteplase, streptokinase
109. Antithrombin III supplementation
Supplement antithrombin to enhance anticoagulation.
Possible treatments: antithrombin III concentrate
110. Heparin-like agents
Exert anticoagulant effects similar to heparin.
Possible treatments: danaparoid
Inflammation & Oxidative Stress Reduction
Mechanisms that reduce tissue damage caused by inflammation and oxidative stress.
111. Nrf2 activation
Enhancing antioxidant pathways to mitigate oxidative damage.
Possible treatments: sulforaphane, bardoxolone methyl, dimethyl fumarate, resveratrol, curcumin, oltipraz
112. 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 damage9.
Possible treatments: doxycycline, minocycline, marimastat, batimastat, quercetin, EGCG, SB-3CT
113. COX-2 inhibition
Suppressing prostaglandin-mediated inflammation.
Possible treatments: celecoxib, etoricoxib, meloxicam, boswellic acids, curcumin
114. NF-κB inhibition
Inhibition of pro-inflammatory transcription factor NF-κB to reduce cytokine production (TLR2/4 blockers overlap here).
Possible treatments: parthenolide, curcumin, quercetin, celastrol, sulforaphane
115. ROS scavenging
Neutralizing reactive oxygen species to prevent oxidative damage.
Possible treatments: vitamin C, vitamin E, melatonin, CoQ10, N-acetylcysteine, alpha-lipoic acid
116. Glutathione enhancement
Boosting endogenous glutathione synthesis or regeneration.
Possible treatments: N-acetylcysteine, alpha-lipoic acid, glutathione, sulforaphane
117. 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)
118. NLRP3 inflammasome inhibition
Blocking NLRP3 activation to reduce inflammatory cytokine release.
Possible treatments: MCC950, glyburide, resveratrol, parthenolide, quercetin
119. SOD mimetics
Mimicking superoxide dismutase to neutralize superoxide radicals.
Possible treatments: tempol, MnTBAP
120. Heme oxygenase-1 (HO-1) induction
Inducing HO-1 to degrade heme and generate cytoprotective molecules.
Possible treatments: curcumin, resveratrol, hemin
121. SIRT1 activation
Activating sirtuins to modulate inflammation and oxidative stress pathways.
Possible treatments: resveratrol, NAD+ precursors, nicotinamide riboside
122. PPAR-γ activation
Activating PPAR-γ to suppress pro-inflammatory signaling.
Possible treatments: pioglitazone, rosiglitazone, curcumin
123. 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 processes17.
Possible treatments: ferrostatin-1, liproxstatin-1, deferoxamine, N-acetylcysteine, vitamin E, ebselen, baicalein
124. 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-1918.
Possible treatments: anti-VCL monoclonal antibodies, vinculin–peptide competitors, small-molecule VCL–actin interface disruptors
125. 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-inflammation14.
Possible treatments: eritoran, resatorvid
Complement System Regulation
Mechanisms that control excessive complement activation, which contributes to inflammation.
126. Complement pathway inhibition
Blocking complement components to reduce inflammation.
Possible treatments: eculizumab, ravulizumab, coversin, zilucoplan, cemdisiran, tesidolumab
127. C3 inhibition
Inhibition of C3 to prevent downstream complement activation.
Possible treatments: pegcetacoplan, AMY-101
128. 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)
129. Classical pathway inhibition
Blocking C1 esterase or C1s to suppress classical pathway activation.
Possible treatments: cinryze, sutimlimab, ruconest
130. C5a signaling blockade
Targeting C5a or its receptor to reduce inflammatory anaphylatoxin effects.
Possible treatments: vilobelimab, avdoralimab, IFX-1, NOX-D21
131. Alternative pathway inhibition
Inhibiting Factor B to disrupt alternative pathway amplification.
Possible treatments: iptacopan, LNP023
132. Alternative pathway suppression
Blocking Factor D to halt alternative pathway activation.
Possible treatments: danicopan, ACH-4471
133. Lectin pathway inhibition
Targeting MASP-2 to inhibit lectin pathway initiation.
Possible treatments: narsoplimab, OMS721
134. Targeted complement regulation
Fusion protein to inhibit complement at sites of activation.
Possible treatments: TT30
135. Broad-spectrum inhibition
Recombinant soluble complement receptor 1 (sCR1) for multi-pathway suppression.
Possible treatments: TP10
Apoptosis & Viral Clearance
Mechanisms that promote the elimination of infected cells or viral components.
136. Apoptosis induction
Triggering programmed cell death in infected cells via Bcl-2 inhibition.
Possible treatments: venetoclax, navitoclax, obatoclax, gossypol
137. Extrinsic apoptosis activation
Activating TRAIL death receptors to induce apoptosis in infected cells.
Possible treatments: conatumumab, dulanermin
138. Fas-mediated apoptosis
Stimulating Fas receptors to trigger caspase-dependent cell death.
Possible treatments: APG101, fas_antibody
139. IAP inhibition
Promoting apoptosis by antagonizing inhibitor of apoptosis proteins (IAPs).
Possible treatments: birinapant, LCL161
140. p53 activation
Restoring p53 activity to induce apoptosis in infected cells.
Possible treatments: nutlin-3a, PRIMA-1MET
141. Autophagy stimulation
Enhancing mTOR-independent/AMPK-mediated degradation of viral components.
Possible treatments: rapamycin, everolimus, spermidine, resveratrol, metformin, trehalose
142. Efferocytosis enhancement
Promoting phagocytic clearance of apoptotic cells containing viral material.
Possible treatments: annexin_A1, resolvin_E1, meritastat
143. Immunogenic cell death
Inducing apoptosis with enhanced antigen presentation for immune clearance.
Possible treatments: oxaliplatin, doxorubicin
Immune Evasion Countermeasures
Mechanisms that counteract SARS-CoV-2's ability to suppress host immunity.
144. Viral immune modulation inhibition
Blocking viral proteins that suppress host immunity.
145. Restoring interferon signaling
Countering viral antagonism of STAT1/IRF pathways to reinstate endogenous interferon responses.
Possible treatments: interferon-beta
146. NSP3 deubiquitinase inhibitors
Blocking NSP3's immune evasion via deubiquitinase activity.
147. ORF6 protein inhibitors
Neutralizing ORF6-mediated interferon suppression.
148. NSP1 translation inhibition
Preventing NSP1 from blocking host translation.
149. 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 lungs19.
Possible treatments: KYA1797K, IWP-O1, LGK-974, Wnt-C59, NCB-0846, ETC-1922159, Pyrvinium, E7449, iCRT-14, SM04690
Antiviral Peptides
Mechanisms involving peptides that directly inhibit viral activity.
150. Defensins
Antimicrobial peptides with potential antiviral effects.
Possible treatments: Human neutrophil peptide-1 (HNP-1)
151. Fusion inhibitor peptides
Peptides blocking viral fusion with host membranes.
Possible treatments: EK1C4
152. Lactoferrin
Iron-binding protein with antiviral properties.
Possible treatments: bovine lactoferrin
153. Cathelicidin peptides
Antimicrobial peptide disrupting viral envelopes.
Possible treatments: LL-37
154. Hepcidin
Liver-produced peptide with immunomodulatory effects.
Possible treatments: hepcidin-25
155. TAT-based peptides
Cell-penetrating peptides disrupting viral assembly.
Possible treatments: TAT-SARS2
RNA Interference
Mechanisms that silence viral genes to inhibit replication.
156. siRNA therapy
Small interfering RNAs targeting viral genes.
Possible treatments: siRNA against RdRp
157. siRNA targeting spike
Silencing spike gene to prevent viral entry.
Possible treatments: siRNA-Spike
158. siRNA targeting nucleocapsid
Inhibiting nucleocapsid gene to disrupt virion formation.
Possible treatments: siRNA-N
159. shRNA therapies
Sustained gene silencing via short hairpin RNA.
Possible treatments: shRNA-ORF1ab
160. miRNA mimics
Using microRNAs to target viral RNA degradation.
Possible treatments: miR-23b
161. 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.
Possible treatments: miR-181 mimic, miR-874 mimic, miR-155 mimic, miR-27a mimic, miR-1290 antagonist, miR-576 inhibitor
References
Manikyam et al., INP-Guided Network Pharmacology Discloses Multi-Target Therapeutic Strategy Against Cytokine and IgE Storms in the SARS-CoV-2 NB.1.8.1 Variant, Research Square, doi:10.21203/rs.3.rs-6819274/v1.
Ilyas et al., Deep Learning-Based Comparative Prediction and Functional Analysis of Intrinsically Disordered Regions in SARS-CoV-2, International Journal of Molecular Sciences, doi:10.3390/ijms26073411.
Hosseini et al., Neuropilin‐1 as a Neuroinflammatory Entry Factor for SARS‐CoV‐2 Is Attenuated in Vaccinated COVID‐19 Patients: A Case–Control Study, Health Science Reports, doi:10.1002/hsr2.70630.
Sanchez et al., Cellular Receptor Tyrosine Kinase Signaling Plays Important Roles in SARS-CoV-2 Infection, Pathogens, doi:10.3390/pathogens14040333.
Mothae et al., SARS-CoV-2 host-pathogen interactome: insights into more players during pathogenesis, Virology, doi:10.1016/j.virol.2025.110607.
Lundrigan et al., Monitoring SARS-CoV-2 Nsp13 helicase binding activity using expanded genetic code techniques, RSC Chemical Biology, doi:10.1039/d4cb00230j.
Bajaj et al., Identification of acrylamide-based covalent inhibitors of SARS-CoV-2 (SCoV-2) Nsp15 using high-throughput screening and machine learning, RSC Advances, doi:10.1039/d4ra06955b.
Baazim et al., FABP4 as a therapeutic host target controlling SARS-CoV-2 infection, EMBO Molecular Medicine, doi:10.1038/s44321-024-00188-x.
Yang et al., Identification and validation of programmed cell death related biomarkers for the treatment and prevention COVID-19, Annals of Medicine, doi:10.1080/07853890.2025.2492830.
Zhang et al., Rho-GTPases subfamily: cellular defectors orchestrating viral infection, Cellular & Molecular Biology Letters, doi:10.1186/s11658-025-00722-w.
Dirvin et al., Identification and targeting of regulators of SARS-CoV-2–host interactions in the airway epithelium, Science Advances, doi:10.1126/sciadv.adu2079.
Muneer et al., Targeting G9a-m6A translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae, iScience, doi:10.1016/j.isci.2025.112632.
Reis et al., Early Treatment with Pegylated Interferon Lambda for Covid-19, New England Journal of Medicine, doi:10.1056/NEJMoa2209760.
Nazir et al., Innate immunity, therapeutic targets and monoclonal antibodies in SARS-CoV-2 infection, PeerJ, doi:10.7717/peerj.19462.
von Ameln Lovison et al., Unveiling the role of the upper respiratory tract microbiome in susceptibility and severity to COVID-19, Frontiers in Cellular and Infection Microbiology, doi:10.3389/fcimb.2025.1531084.
Nishimura et al., Possible involvement of neuropeptide Y sub-receptor 1 (NPY-Y1) in the anti-viral response of SARS-CoV-2 infection in Syrian hamster, Biomedical Research, doi:10.2220/biomedres.46.37.
Mao et al., Critical role of ferroptosis in viral infection and host responses, Virology, doi:10.1016/j.virol.2025.110485.
Xue et al., VCL/ICAM-1 pathway is associated with lung inflammatory damage in SARS-CoV-2 Omicron infection, Nature Communications, doi:10.1038/s41467-025-59145-y.
Xu et al., The Wnt/β-catenin pathway is important for replication of SARS-CoV-2 and other pathogenic RNA viruses, npj Viruses, doi:10.1038/s44298-024-00018-4.
Ranches et al., Differentially expressed ncRNAs as key regulators in infection of human bronchial epithelial cells by the SARS-CoV-2 Delta variant, Molecular Therapy Nucleic Acids, doi:10.1016/j.omtn.2025.102559.
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