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, recombinant ACE2 decoys
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 fusion.
Possible treatments: umifenovir, arbidol, nelfinavir
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 entry1.
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 docking.
Possible treatments: lisinopril, losartan, valsartan, enalapril, telmisartan, resveratrol, berberine, estradiol, melatonin, artefenomel
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. Lectin binding agents
Lectins that bind viral glycoproteins to block entry.
Possible treatments: griffithsin
15. 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
16. Cathepsin L block
Inhibit endosomal protease cathepsin L (alternative pathway for spike activation).
Possible treatments: teicoplanin, MDL-28170, E-64d (aloxistatin)
17. Integrin targeting
Block integrin receptors (e.g., α5β1, αvβ3) involved in ACE2-independent entry.
Possible treatments: cilengitide, SB273005, RGD peptide inhibitors
18. Neuropilin-1 blockade
Inhibit NRP1 co-receptor binding to limit spike protein interaction.
Possible treatments: EG00229, VEGF-A inhibitors
19. Lipid raft disruption
Deplete membrane cholesterol to destabilize lipid raft-dependent entry mechanisms.
Possible treatments: simvastatin, fluvastatin, methyl-β-cyclodextrin, 25-hydroxycholesterol
20. Surfactant inactivation
Disrupt viral envelopes or spike-receptor interactions via surfactant activity.
Possible treatments: poloxamers, chlorhexidine
21. Endocytosis/acidification block
Inhibit clathrin-mediated endocytosis or endosomal acidification to prevent viral internalization.
Possible treatments: chloroquine, hydroxychloroquine, dynasore, mitmab, bafilomycin A1, umifenovir
22. Furin inhibition
Block furin-mediated cleavage of the spike protein to impair viral entry.
Possible treatments: decanoyl-RVKR-chloromethylketone, MI-1851, naphthofluorescein
Mechanisms that disrupt the replication or assembly of SARS-CoV-2 within host cells.
Replication inhibition mechanisms targeting viral proteins.
23. RNA-dependent RNA polymerase (RdRp) inhibition
Nucleoside analogs interfere with viral RNA synthesis.
Possible treatments: remdesivir, molnupiravir, azvudine, bemnifosbuvir, deuremidevir, favipiravir, ribavirin, galidesivir
24. Non-nucleoside RdRp inhibition
Bind to allosteric sites on RdRp to disrupt RNA synthesis.
Possible treatments: suramin, dasabuvir, PPI-383
25. 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
26. Papain-like protease (PLpro) inhibition
Blocking PLpro activity, which processes viral polyproteins and disrupts host immune response.
Possible treatments: GRL-0617, thiopurine analogs, diiodohydroxyquinoline
27. Helicase inhibition
Inhibiting the viral helicase enzyme needed to unwind RNA for replication.
Possible treatments: ivermectin, SSYA10-001, bananin
28. Methyltransferase inhibition
Inhibit viral RNA capping by targeting nsp10/nsp16 complex.
Possible treatments: sinefungin, SAM analogs
29. Ion channel (E protein) blockade
Disrupting the SARS-CoV-2 envelope (E) protein function.
Possible treatments: amantadine, rimantadine, hexamethylene amiloride
30. Nucleocapsid (N) protein inhibition
Disrupt N protein's RNA binding and oligomerization, preventing viral genome packaging.
Possible treatments: ebselen, PJ34, hesperetin
31. 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 packaging1.
Possible treatments: RNA-binding inhibitors, LLPS disruptors, phase separation modulators, condensate destabilizers
32. Virion assembly disruption
Inhibit assembly of viral structural proteins and RNA into new virions.
Possible treatments: nitazoxanide, temoporfin
33. 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
34. 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 inhibition1.
Possible treatments: designed peptidomimetics, small molecules stabilizing disorder-to-order transitions
35. 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 function1.
Possible treatments: metal chelators, Cu(II) mimetics, W161/H165-targeting compounds
36. 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
37. 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
38. 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
39. 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
40. 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
41. 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
42. 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
43. 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
44. 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
45. 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, aurintricarboxylic acid, thymoquinone, gossypol, SAM analogs
46. Nsp15 Endoribonuclease Inhibition
Mechanisms that target the viral endoribonuclease Nsp15, which helps SARS-CoV-2 evade host immune detection2.
Possible treatments: acrylamide-based covalent inhibitors
47. 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
48. 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
49. 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 evasion1.
Possible treatments: small molecules disrupting membrane localization, peptidomimetics, subcellular targeting disruptors
50. 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 storms1.
Possible treatments: TRAF interaction inhibitors, selective NF-κB modulators, NLRP3 pathway disruptors
51. 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
52. 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
53. 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
54. 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
55. 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.
56. Nucleotide depletion
Inducing viral mutagenesis or depleting nucleotide pools.
Possible treatments: molnupiravir
57. GTP depletion
Inhibition of IMP dehydrogenase depleting guanosine nucleotides.
Possible treatments: ribavirin, mycophenolate mofetil
58. Pyrimidine depletion
Inhibition of dihydroorotate dehydrogenase depleting pyrimidine nucleotides.
Possible treatments: leflunomide, teriflunomide
59. Deoxyribonucleotide depletion
Inhibition of ribonucleotide reductase reducing deoxyribonucleotide pools.
Possible treatments: hydroxyurea
60. Glucose deprivation
Competitive inhibition of glucose metabolism to limit viral energy sources.
Possible treatments: 2-deoxy-D-glucose
61. Amino acid depletion
Depletion of asparagine to inhibit viral protein synthesis.
Possible treatments: asparaginase
62. Iron chelation
Sequestration of iron to limit availability for viral replication.
Possible treatments: deferoxamine
63. Methyl donor depletion
Inhibition of S-adenosylmethionine synthesis impairing viral RNA methylation.
Possible treatments: cycloleucine
64. Glutamine antagonism
Inhibition of glutamine metabolism to reduce nucleotide precursors.
Possible treatments: 6-diazo-5-oxo-L-norleucine
65. Cholesterol depletion
Reducing cellular cholesterol to impair viral entry and assembly.
Possible treatments: simvastatin, atorvastatin, hydroxypropyl-beta-cyclodextrin
66. 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)3.
Possible treatments: BMS309403, CRE-14
Host Immune Modulation
Mechanisms that modulate the host immune response to enhance antiviral activity or reduce immunopathology.
67. Cytokine storm suppression
Anti-inflammatory agents target cytokine pathways (IL-1/IL-6/JAK-STAT/TNF-α/complement) or inflammasomes to mitigate excessive inflammation.
Possible treatments: dexamethasone, methylprednisolone, tocilizumab, sarilumab, baricitinib, ruxolitinib, anakinra, canakinumab, infliximab, adalimumab, colchicine, lenzilumab, eculizumab
68. Interferon signaling enhancement
Boosting type I/II/III interferons or enhancing interferon pathway activation to stimulate antiviral responses.
Possible treatments: interferon-beta, interferon-alpha, peginterferon-lambda, interferon-gamma, nitazoxanide
69. 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
70. Innate immune stimulation
Activating innate immunity via PRRs (TLRs, RIG-I, STING) or antiviral effector mechanisms.
Possible treatments: imiquimod, resiquimod, polyinosinic-polycytidylic acid (poly I:C), monophosphoryl lipid A, CpG oligonucleotides
71. Micronutrient supplementation for immune system support
Vitamins, minerals, and cofactors essential for immune cell function and signaling.
Possible treatments: vitamin A, vitamin C, vitamin D, vitamin E, vitamin B6, vitamin B12, zinc, selenium, iron, copper, magnesium
72. Immune regulation
Modulating regulatory immune cells (e.g., Tregs) or checkpoint pathways to balance inflammation.
Possible treatments: low-dose interleukin-2, abatacept, sirolimus
73. 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-194.
Possible treatments: BIBO3304, BIBP3226
Hemostasis & Thrombosis Management
Mechanisms that address coagulopathy and prevent thrombosis, common in severe COVID-19.
74. Anticoagulant therapy
Preventing microthrombi formation in severe cases.
Possible treatments: heparin, enoxaparin, dalteparin, tinzaparin
75. Antiplatelet therapy
Reducing platelet aggregation to prevent clots.
Possible treatments: aspirin, clopidogrel
76. Direct thrombin inhibitors
Inhibit thrombin activity to prevent fibrin formation.
Possible treatments: dabigatran, argatroban, bivalirudin
77. Direct factor Xa inhibitors
Directly inhibit factor Xa to reduce thrombin generation.
Possible treatments: rivaroxaban, apixaban, edoxaban
78. Indirect factor Xa inhibitors
Enhance antithrombin-mediated inhibition of factor Xa.
Possible treatments: fondaparinux
79. Vitamin K antagonists
Inhibit synthesis of vitamin K-dependent clotting factors.
Possible treatments: warfarin
80. P2Y12 receptor inhibitors
Block ADP-induced platelet activation and aggregation.
Possible treatments: clopidogrel, prasugrel, ticagrelor, ticlopidine
81. Glycoprotein IIb/IIIa inhibitors
Prevent fibrinogen binding and platelet cross-linking.
Possible treatments: abciximab, eptifibatide, tirofiban
82. Phosphodiesterase inhibitors
Increase cAMP levels, reducing platelet activation.
Possible treatments: dipyridamole, cilostazol
83. Protease-activated receptor-1 antagonists
Inhibit thrombin-induced platelet aggregation.
Possible treatments: vorapaxar
84. Fibrinolytic agents
Lyse existing thrombi by converting plasminogen to plasmin.
Possible treatments: alteplase, tenecteplase, reteplase, streptokinase
85. Antithrombin III supplementation
Supplement antithrombin to enhance anticoagulation.
Possible treatments: antithrombin III concentrate
86. 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.
87. Nrf2 activation
Enhancing antioxidant pathways to mitigate oxidative damage.
Possible treatments: sulforaphane, bardoxolone methyl, dimethyl fumarate, resveratrol, curcumin, oltipraz
88. Matrix metalloproteinase (MMP) inhibition
Reducing inflammation and vascular leakage.
Possible treatments: doxycycline, minocycline, marimastat, batimastat, quercetin, EGCG
89. COX-2 inhibition
Suppressing prostaglandin-mediated inflammation.
Possible treatments: celecoxib, etoricoxib, meloxicam, boswellic acids, curcumin
90. NF-κB inhibition
Inhibition of pro-inflammatory transcription factor NF-κB to reduce cytokine production.
Possible treatments: parthenolide, curcumin, quercetin, celastrol, sulforaphane
91. ROS scavenging
Neutralizing reactive oxygen species to prevent oxidative damage.
Possible treatments: vitamin C, vitamin E, melatonin, CoQ10, N-acetylcysteine, alpha-lipoic acid
92. Glutathione enhancement
Boosting endogenous glutathione synthesis or regeneration.
Possible treatments: N-acetylcysteine, alpha-lipoic acid, glutathione, sulforaphane
93. NLRP3 inflammasome inhibition
Blocking NLRP3 activation to reduce inflammatory cytokine release.
Possible treatments: MCC950, glyburide, resveratrol, parthenolide, quercetin
94. SOD mimetics
Mimicking superoxide dismutase to neutralize superoxide radicals.
Possible treatments: tempol, MnTBAP
95. Heme oxygenase-1 (HO-1) induction
Inducing HO-1 to degrade heme and generate cytoprotective molecules.
Possible treatments: curcumin, resveratrol, hemin
96. SIRT1 activation
Activating sirtuins to modulate inflammation and oxidative stress pathways.
Possible treatments: resveratrol, NAD+ precursors, nicotinamide riboside
97. PPAR-γ activation
Activating PPAR-γ to suppress pro-inflammatory signaling.
Possible treatments: pioglitazone, rosiglitazone, curcumin
98. 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 processes5.
Possible treatments: ferrostatin-1, liproxstatin-1, deferoxamine, N-acetylcysteine, vitamin E, ebselen, baicalein
Complement System Regulation
Mechanisms that control excessive complement activation, which contributes to inflammation.
99. Complement pathway inhibition
Blocking complement components to reduce inflammation.
Possible treatments: eculizumab, ravulizumab, coversin, zilucoplan, cemdisiran, tesidolumab
100. C3 inhibition
Inhibition of C3 to prevent downstream complement activation.
Possible treatments: pegcetacoplan, AMY-101
101. Classical pathway inhibition
Blocking C1 esterase or C1s to suppress classical pathway activation.
Possible treatments: cinryze, sutimlimab, ruconest
102. C5a signaling blockade
Targeting C5a or its receptor to reduce inflammatory anaphylatoxin effects.
Possible treatments: vilobelimab, avdoralimab, IFX-1, NOX-D21
103. Alternative pathway inhibition
Inhibiting Factor B to disrupt alternative pathway amplification.
Possible treatments: iptacopan, LNP023
104. Alternative pathway suppression
Blocking Factor D to halt alternative pathway activation.
Possible treatments: danicopan, ACH-4471
105. Lectin pathway inhibition
Targeting MASP-2 to inhibit lectin pathway initiation.
Possible treatments: narsoplimab, OMS721
106. Targeted complement regulation
Fusion protein to inhibit complement at sites of activation.
Possible treatments: TT30
107. Broad-spectrum inhibition
Recombinant soluble complement receptor 1 (sCR1) for multi-pathway suppression.
Possible treatments: TP10
Host Nutrient & Factor Modulation
Mechanisms aimed at manipulating the availability or metabolism of host-derived nutrients and factors essential for viral replication or survival.
108. Zinc supplementation
Potentially interfering with viral replication.
Possible treatments: zinc sulfate, zinc gluconate
109. Cholesterol depletion
Reducing cellular cholesterol to impair viral entry and assembly.
Possible treatments: simvastatin, atorvastatin, hydroxypropyl-beta-cyclodextrin
110. Selenium supplementation
Enhancing antioxidant defenses and potentially inhibiting viral replication.
Possible treatments: sodium selenite, selenomethionine
Apoptosis & Viral Clearance
Mechanisms that promote the elimination of infected cells or viral components.
111. Apoptosis induction
Triggering programmed cell death in infected cells via Bcl-2 inhibition.
Possible treatments: venetoclax, navitoclax, obatoclax, gossypol
112. Extrinsic apoptosis activation
Activating TRAIL death receptors to induce apoptosis in infected cells.
Possible treatments: conatumumab, dulanermin
113. Fas-mediated apoptosis
Stimulating Fas receptors to trigger caspase-dependent cell death.
Possible treatments: APG101, fas_antibody
114. IAP inhibition
Promoting apoptosis by antagonizing inhibitor of apoptosis proteins (IAPs).
Possible treatments: birinapant, LCL161
115. p53 activation
Restoring p53 activity to induce apoptosis in infected cells.
Possible treatments: nutlin-3a, PRIMA-1MET
116. Autophagy stimulation
Enhancing mTOR-independent/AMPK-mediated degradation of viral components.
Possible treatments: rapamycin, everolimus, spermidine, resveratrol, metformin, trehalose
117. Efferocytosis enhancement
Promoting phagocytic clearance of apoptotic cells containing viral material.
Possible treatments: annexin_A1, resolvin_E1, meritastat
118. 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.
119. Viral immune modulation inhibition
Blocking viral proteins that suppress host immunity.
120. Exogenous interferon therapy
Supplementing interferons to overcome viral suppression.
Possible treatments: interferon-beta
121. STING pathway agonists
Activating STING to enhance interferon production.
Possible treatments: DMXAA
122. NSP3 deubiquitinase inhibitors
Blocking NSP3's immune evasion via deubiquitinase activity.
123. ORF6 protein inhibitors
Neutralizing ORF6-mediated interferon suppression.
124. NSP1 translation inhibition
Preventing NSP1 from blocking host translation.
Antiviral Peptides
Mechanisms involving peptides that directly inhibit viral activity.
125. Defensins
Antimicrobial peptides with potential antiviral effects.
Possible treatments: Human neutrophil peptide-1 (HNP-1)
126. Fusion inhibitor peptides
Peptides blocking viral fusion with host membranes.
Possible treatments: EK1C4
127. Lactoferrin
Iron-binding protein with antiviral properties.
Possible treatments: bovine lactoferrin
128. Cathelicidin peptides
Antimicrobial peptide disrupting viral envelopes.
Possible treatments: LL-37
129. Hepcidin
Liver-produced peptide with immunomodulatory effects.
Possible treatments: hepcidin-25
130. TAT-based peptides
Cell-penetrating peptides disrupting viral assembly.
Possible treatments: TAT-SARS2
RNA Interference
Mechanisms that silence viral genes to inhibit replication.
131. siRNA therapy
Small interfering RNAs targeting viral genes.
Possible treatments: siRNA against RdRp
132. siRNA targeting spike
Silencing spike gene to prevent viral entry.
Possible treatments: siRNA-Spike
133. siRNA targeting nucleocapsid
Inhibiting nucleocapsid gene to disrupt virion formation.
Possible treatments: siRNA-N
134. shRNA therapies
Sustained gene silencing via short hairpin RNA.
Possible treatments: shRNA-ORF1ab
135. miRNA mimics
Using microRNAs to target viral RNA degradation.
Possible treatments: miR-23b
References
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.
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.
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.
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