Table 1.
Severe Acute Respiratory Syndrome-coronavirus (SARS-CoV) antivirals: Targets and mechanisms of action.
| Target of Antivirals | Example/s | Mechanism of Action |
|---|---|---|
| Viral Entry | ||
| • Spike (S) protein | Monoclonal Antibodies such as S230.15, m396, S109.8 S227.14, S230.15, 80R scFv, CR3022 CR3014, 33G4 35B5, 30F9, 4D4, IF8, 5E9, and B1 scFv | Most of the antibodies bind to S1 domain of SARS-CoV S protein and block its binding to ACE2 on target cells. Antibodies, such as 4D4, bind to regions other than RBD and block a post-attachment step in viral entry. Others (1F8, 5E9, and B1) bind to S2 domain and inhibit viral envelope-cell membrane fusion |
| Convalescent plasma | Contains neutralizing antibodies that bind to different regions on SARS-CoV S protein and inhibit viral entry by different mechanisms | |
| Lectins: Griffithsin (a lectin isolated from the red alga Griffithsia spp.) and Urtica dioica agglutinin (UDA) (a lectin isolated from Urtica dioca) | Bind to SARS-CoV S protein and inhibit binding of SARS-CoV to ACE2 | |
| Synthetic peptides derived from ACE2 and soluble ACE2 ectodomain | Bind to SARS-CoV S protein and inhibit attachment to target cells | |
| Synthetic peptides derived from HR1 or HR2 regions of S2 domain e.g. CP-1 peptide. | Bind to S2 domain and block fusion of viral envelope with cell membrane | |
| Imatinib (Abl kinase inhibitor) | Blocks fusion of viral envelope with cell membrane | |
| Chinese herbal medicine molecules tetra-O-galloyl-beta-D-glucose (TGG) and luteolin | Bind to S2 domain and inhibit fusion | |
| Emodin (a plant anthraquinone) | Binds to SARS-CoV S protein and blocks its interaction with ACE2 | |
|
• Angiotensin-converting enzyme 2
(ACE2) |
N-(2-aminoethyl)-1-aziridineethanamine (NAAE) | Inhibits ACE2 activity and blocks fusion |
| • Clathrin-mediated endocytosis | Chlorpromazine | Inhibits viral entry by blocking clathrin-mediated endocytosis of viral particles |
| • Endosomes | Chloroquine and P9 peptide |
Raise the pH of the endosome and thus inhibit viral entry by blocking cathepsin L-mediated cleavage of S protein |
| • Cathepsin L | Small molecules such as E-64D and 5705213 | Inhibit cathepsin L and thus inhibits cathepsin L-mediated cleavage of S protein |
|
• Transmembrane Serine Protease 2
(TMPRSS2) |
Camostat mesylate | Blocks TMPRSS2 and thus inhibits processing of SARS-CoV S protein and viral entry at plasma membrane |
|
RNA-dependent RNA polymerase
(RdRp) |
Nucleoside analogs: β-D-N4-hydroxycitidine, galidesivir also known as BCX4430 or immucillin-A, and remdesivir | Inhibit RdRp leading to premature termination of RNA synthesis |
| Nucleoside analogs: 6-azauridine and pyrazofurin | Inhibit orotidine monophosphate decarboxylase which leads to depletion of pyrimidine nucleosides pool | |
| Nucleoside analog: ribavirin | Ribavirin gets incorporated into the newly synthesized RNA chain resulting in viral lethal mutations. It is also believed to inhibit cellular inosine monophosphate dehydrogenase resulting in depletion of intracellular GTP which leads to inhibition of mRNA cap synthesis | |
| Viral helicase | Bananins | Inhibit ATPase activity of viral helicase and thus blocks viral replication |
| Bismuth complexes | Inhibit ATPase and unwinding activities of viral helicase | |
| Falvonoids such as myricetin and scutellarein | Inhibit ATPase activity of viral helicase. | |
| Small molecule SSYA10-001 | Inhibits unwinding activity of viral helicase | |
| Viral proteases | ||
| • Picornavirus 3-chymotrypsin-like protease (3CLpro) | HIV-1 protease inhibitors; lopinavir/ritonavir and nelfinavir | One of the mechanisms is inhibition of 3CLpro activity which leads to inhibition of processing of SARS-CoV polyproteins and blockage of viral replication. Other mechanisms involve inhibition of the cellular enzymes; calpains |
| Cinanserin (a serotonin antagonist), esculetin-4-carboxylic acid ethyl ester (a marine natural product; coumarin derivative), plant-derived compounds such as betulinic acid (sesquiterpenoid) and savinin (lignoid), quinone-methide trit-erpenes isolated from Tripterygium regelii, dieckol (a phlorotannin) isolated from brown algae Ecklonia cava, alkylated chalcones from Angelica keiskei, flavonoids such as herbacetin, rhoifolin and pectolinarin, and pyrazolone compounds | Inhibit 3CLpro and thus inhibit viral replication | |
|
• Papain-like protease 2
(PLpro) |
Diarylheptanoids from Alnus japonica and geranylated flavonoids from Paulownia tree, 6-mercaptopurine (6-MP), 6-thioguanine (6-TG), and disulfiram |
Inhibit viral replication by blocking PLpro and processing of viral polyproteins |
|
Cellular proteases:
Calpain |
Z-Val-Phe-Ala-CHO (calpain inhibitor III) and Val-Leu-CHO (calpain inhibitor VI) | Inhibit calpains and thus inhibit viral replication and virus-induced apoptosis |
| Miscellaneous Antivirals | E, M, N, ORF3a, ORF7a, and ORF7b siRNAs | Inhibit viral replication by inducing the breakdown of viral mRNAs |
| Hexamethylene amiloride | Blocks E protein cationic-selective ion channel activity | |
| Aurintricarboxylic acid | Inhibits SARS-CoV attachment to target cells and inhibits viral replication | |
| Rimantadine | Blocks E protein cationic-selective ion channel activity. | |
| Niclosamide | Inhibits replication of SARS-CoV. Mechanism is not well known | |
| Amiodarone | Inhibits post-entry step in viral life cycle | |
| K22 | Inhibits formation of double membrane vesicles | |
| dsRNA-activated caspase oligomerizer (DRACO) | Induces apoptosis in cells that are infected with SARS-CoV by recognizing viral dsRNA intermediates using its viral dsRNA-binding domain | |
| NO donors: 2,2′-(hydroxynitrosihydrazino)bis-ethamine (DETA NONOate) and S-nitroso-N-acetylpenicillamine (SNAP) | Dissociate to produce NO which is antiviral | |
| Cyclosporine A and its analog alisporivir | Form a complex with cyclophilins which leads to inhibition of viral replication. Also, the complex with cyclophilins inhibits calcineurin which blocks T cell activation and subsequent T cell-mediated tissue damage | |
| Geldanamycin (an antibiotic) | Binds to and inhibits heat shock protein 90 (Hsp90) which inhibits SARS-CoV replication | |
| Interferon alpha and beta | Viral RNA degradation, inhibition of protein synthesis, and viral assembly | |
| Glycyrrhizin (triterpenoid saponin glycoside from licorice root) | Inhibits adsorption of viral particles on target cells and induces production of NO. Other antiviral mechanisms need to be explored |