TABLE 2.
The host-based small molecule drugs with therapeutic potentials for CoVs
| Antiviral agent | Drug class and/or targets | Activity against coronaviruses | Ref. |
|---|---|---|---|
| Anisomycin (27) | Protein synthesis inhibitor | SARS-CoV: EC50 = 0.191 μM (Vero E6/MA15) MERS-CoV: EC50 = 0.003 μM (Vero E6/Jordan N3) |
178 |
| Emetine hydrochloride (28) | Protein synthesis inhibitor | SARS-CoV: EC50 = 0.051 μM (Vero E6/MA15) MERS-CoV: EC50 = 0.014 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 0.46 μM, CC50 = 56.46 μM (Vero E6) |
178,214 |
| Homoharringtonine (29) | Protein synthesis inhibitor | MERS-CoV: EC50 = 0.072 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 2.55 μM, CC50 = 59.75 μM (Vero E6) |
178,214 |
| Cyclosporine (30) | Inhibitor of cyclophilins and their interaction with nsp1 | SARS-CoV: EC50 = 3.2 μM, CC50 > 17 μM (Vero E6/Frankfurt-1) MERS-CoV: suppressed induced cytopathic effect at 9 μM in Vero cells with no toxic effect SARS-CoV-2: EC50 = 5.8 μM, CC50 > 50 μM (Vero) |
70,221,224 |
| Alisporivir (31) | Cyclophilin inhibitor | SARS-CoV: EC50 = 8.3 μM, CC50 > 50 μM (Vero E6/Frankfurt-1); EC50 = 1.3 μM (Vero E6/MA15) MERS-CoV: EC50 = 3.6 μM, CC50 = 26.4 μM (Vero/EMC/2012); EC50 = 3.0 μM (Vero/Jordan N3) SARS-CoV-2: EC50 = 0.46 μM, CC50 > 20 μM (Vero E6) |
229,230 |
| Imatinib mesylate (32) | Abl kinase inhibitor | SARS-CoV: EC50 = 9.82 μM, CC50 > 100 μM (Vero E6/MA15) MERS-CoV: EC50 = 17.69 μM, CC50 > 100 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 3.24 μM (MOI = 0.004) and 5.32 μM (MOI = 0.01), CC50 > 30.86 μM (Vero E6) |
178,232 |
| Dasatinib (33) | Abl kinase/Src inhibitor | SARS-CoV: EC50 = 2.10 μM, CC50 > 10 μM (Vero E6/MA15) MERS-CoV: EC50 = 5.47 μM, CC50 > 10 μM (Vero E6/Jordan N3) |
178 |
| Saracatinib (34) | Abl kinase/Src inhibitor | MERS-CoV: EC50 = 2.9 μM, CC50 = 57 μM (Huh-7) | 241 |
| Rapamycin (35) | mTOR inhibitor | Inhibited MERS-CoV infection by ~60% at 10 μM via both pre- and postinfection treatment | 246 |
| Selumetinib (36) | MEK1/2 inhibitors | Inhibited MERS-CoV infection by ~70% at 1 μM via preinfection treatment and by ~90% at 10 μM via postinfection treatment | 246 |
| Trametinib (37) | MEK1/2 inhibitors | Inhibited MERS-CoV infection by ~90% at 0.1 μM via preinfection treatment and by ~70% at 1 μM via postinfection treatment | 246 |
| Baricitinib (38) | JAK and AAK1 inhibitor | Not reported | |
| Abemaciclib (41) | CDK4/6 inhibitor | SARS-CoV-2: EC50 = 6.62 μM, CC50 > 50 μM (Vero) | 70 |
| Gilteritinib (42) | FLT3 and AXL inhibitor | SARS-CoV-2: EC50 = 6.76 μM, CC50 = 37.16 μM (Vero) | 70 |
| K11777 (43) | Cathepsin inhibitor | SARS-CoV: IC50 < 0.05 μM, IC90 = 0.35 μM, CC50 > 105.6 μM (Vero 76/Urbani); IC50 < 0.05 μM, IC90 = 1.04 μM, CC50 = 85.2 μM (Vero 76/Toronto-2); its derivative SMDC256160 showed no in vivo efficacy in a mouse model of SARS-CoV infection | 255 |
| E-64-d (44) | Cathepsin inhibitor | SARS-CoV: EC50 = 0.76 μM (Vero E6/MA15) MERS-CoV: EC50 = 1.275 μM (Vero E6/Jordan N3) Inhibited SARS-CoV-2 entry |
38,178 |
| Camostat (46) | TMPRSS2 inhibitor | Reduced the infection of SARS-CoV, MERS-CoV, and SARS-CoV-2 in Calu-3 cells; showed in vivo efficacy in a mouse model of SARS-CoV infection (30 mg/kg, oral, BID, 9 days) | 41,50,53,255 |
| Nafamostat (47) | TMPRSS2 inhibitor | MERS-CoV: reduced the entry and replication at 0.1 μM in Calu-3 cells SARS-CoV-2: EC50 = 22.50 μM, CC50 > 100 μM (Vero E6) |
110,270 |
| Chloroquine hydrochloride (48) | Antiparasitic/inhibit host receptor glycosylation and endosomal acidification | SARS-CoV: EC50 = 6.54 μM (Vero E6/MA15); EC50 = 4.0 μM, CC50 > 128 μM (Vero E6/Frankfurt-1) MERS-CoV: EC50 = 6.28 μM (Vero E6/Jordan N3); EC50 = 3.0 μM, CC50 = 58.1 μM (Huh-7/EMC/2012) SARS-CoV-2: EC50 = 1.13 μM, CC50 > 100 μM (Vero E6) |
62,110,178 |
| Hydroxychloroquine sulfate (49) | SARS-CoV: EC50 = 6.54 μM (Vero E6/MA15) MERS-CoV: EC50 = 6.28 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 4.51 μM (MOI = 0.01) and 12.96 μM (MOI = 0.8), CC50 = 249.5 μM (Vero E6); EC50 at 48 h = 0.72 μM (MOI = 0.01) in Vero cells |
178,281,282 | |
| Mefloquine (50) | SARS-CoV: EC50 = 15.55 μM (Vero E6/MA15) MERS-CoV: EC50 = 7.42 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 4.33 μM, CC50 = 13.97 μM (Vero) |
70,178 | |
| Amodiaquine (51) | SARS-CoV: EC50 = 1.27 μM (Vero E6/MA15) MERS-CoV: EC50 = 6.21 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 5.15 μM, CC50 > 50 μM (Vero) |
70,178 | |
| Chlorpromazine hydrochloride (52) | Antipsychotic or antihistamine or antiemetic/phenothiazine/inhibit clathrin-mediated endocytosis | SARS-CoV: EC50 = 12.97 μM, CC50 > 100 μM (Vero E6/MA15); EC50 = 8.8 μM, CC50 = 24.3 μM (Vero E6/Frankfurt-1) MERS-CoV: EC50 = 9.51 μM (Vero E6/Jordan N3); EC50 = 4.9 μM, CC50 = 21.3 μM (Huh-7/EMC/2012) SARS-CoV-2: EC50 = 3.14 μM (MOI = 0.004) and 4.03 μM (MOI = 0.01), CC50 = 11.88 μM (Vero E6) |
62,178,232 |
| Triflupromazine hydrochloride (53) | SARS-CoV: EC50 = 6.40 μM, CC50 > 10 μM (Vero E6/MA15) MERS-CoV: EC50 = 5.76 μM (Vero E6/Jordan N3) |
178 | |
| Fluphenazine hydrochloride (54) | SARS-CoV: EC50 = 21.43 μM (Vero E6/MA15) MERS-CoV: EC50 = 5.87 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 6.36 μM (MOI = 0.004) and 8.98 μM (MOI = 0.01), CC50 = 20.02 μM (Vero E6) |
178,232 | |
| Thiothixene (55) | SARS-CoV: EC50 = 5.32 μM (Vero E6/MA15) MERS-CoV: EC50 = 9.30 μM (Vero E6/Jordan N3) |
178 | |
| Promethazine hydrochloride (56) | SARS-CoV: EC50 = 7.55 μM (Vero E6/MA15) MERS-CoV: EC50 = 11.80 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 9.21 μM (MOI = 0.004) and 10.44 μM (MOI = 0.01), CC50 = 42.59 μM (Vero E6) |
178,232 | |
| Thiethylperazine maleate (57) | MERS-CoV: EC50 = 7.87 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 7.09 μM (MOI = 0.004) and 8.02 μM (MOI = 0.01), CC50 = 18.37 μM (Vero E6) |
178,232 | |
| Ouabain (58) | Cardiotonic steroids/target ATP1A1 and inhibit CoV entry | Inhibited MERS-CoV infection at 50 nM via preinfection SARS-CoV-2: EC50 < 0.097 μM, CC50 > 50 μM (Vero) |
70,302 |
| Bufalin (59) | Inhibited MERS-CoV infection at 10–15 nM via preinfection | 302 | |
| Proscillaridin (60) | SARS-CoV-2: EC50 = 2.04 μM, CC50 > 50 μM (Vero) | 70 | |
| Digoxin (61) | SARS-CoV-2: EC50 = 0.19 μM, CC50 > 50 μM (Vero) | 70 | |
| Digitoxin (62) | SARS-CoV-2: EC50 = 0.23 μM, CC50 > 50 μM (Vero) | 70 | |
| Clomipramine hydrochloride (63) | Tricyclic antidepressant/inhibit clathrin-dependent entry | SARS-CoV: EC50 = 13.24 μM (Vero E6/MA15) MERS-CoV: EC50 = 9.33 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 5.63 μM (MOI = 0.004) and 7.59 μM (MOI = 0.01), CC50 > 29.68 μM (Vero E6) |
178,232 |
| Tamoxifen citrate (64) | Estrogen receptor modulator/inhibit CoV entry | SARS-CoV: EC50 = 92.89 μM (Vero E6/MA15) MERS-CoV: EC50 = 10.12 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 34.12 μM (MOI = 0.004) and 8.98 μM (MOI = 0.01), CC50 = 37.96 μM (Vero E6) |
178,232 |
| Toremifene citrate (65) | SARS-CoV: EC50 = 11.97 μM, CC50 > 100 μM (Vero E6/MA15) MERS-CoV: EC50 = 12.92 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 4.77 μM (MOI = 0.004) and 11.30 μM (MOI = 0.01), CC50 = 20.51 μM (Vero E6) |
178,232 | |
| Astemizole (66) | Antihistamine and anticholinergic/inhibit CoV entry | SARS-CoV: EC50 = 5.59 μM (Vero E6/MA15) MERS-CoV: EC50 = 4.88 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = ~1.1 μM (Vero E6) |
178,304 |
| Chlorphenoxamine (67) | SARS-CoV: EC50 = 20.03 μM (Vero E6/MA15) MERS-CoV: EC50 = 12.65 μM (Vero E6/Jordan N3) |
178 | |
| Niclosamide (68) | Anthelmintic drug/broad antiviral agent | SARS-CoV: EC50 < 0.1 μM, CC50 = 22.1 μM (Vero E6) SARS-CoV-2: EC50 = 0.28 μM, CC50 > 50 μM (Vero) Suppressed MERS-CoV infection by ~1000-fold at 48 h at 10 μM |
70,308,309 |
| Nitazoxanide (69) | Broad antiparasitic and antiviral drug/induce the host innate immune response | SARS-CoV-2: EC50 = 2.12 μM, CC50 = 35.53 μM (Vero E6) | 110,312 |
| Hexachlorophene (71) | Disinfectant | SARS-CoV-2: EC50 = 0.90 μM, CC50 = 19.3 μM (Vero) | 70 |
| Tilorone (72) | Antiviral drug/interferon inducer | MERS-CoV: EC50 = 10.56, CC50 > 20 μM (Vero E6) SARS-CoV-2: EC50 = 4.09 μM, CC50 = 19.67 μM (Vero) |
70,322 |
| Terconazole (73) | Antifungal drug | SARS-CoV: EC50 = 15.33 μM (Vero E6/MA15) MERS-CoV: EC50 = 12.20 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 11.92 μM (MOI = 0.004) and 16.14 μM (MOI = 0.01), CC50 = 41.46 μM (Vero E6) |
178,232 |
| Azithromycin (74) | Antibiotic/macrolide | Not reported | |
| Salinomycin sodium (75) | Polyether ionophore antibiotic | MERS-CoV: EC50 = 5.49, CC50 = 3.84 μM (Vero E6) SARS-CoV-2: EC50 = 0.24 μM, CC50 > 50 μM (Vero) |
70,322 |
| Ivermectin (76) | Antiparasitic/broad antiviral agent | SARS-CoV-2: EC50 = ~2.0 μM (Vero hSLAM/Australia/VIC01/2020) | 336 |
| Anidulafungin (77) | Antifungal/semisynthetic echinocandin | SARS-CoV-2: EC50 = 4.64 μM, CC50 > 50 μM (Vero) | 70 |
| Benztropine (78) | Anticholinergic | SARS-CoV: EC50 = 21.61 μM (Vero E6/MA15) MERS-CoV: EC50 = 16.63 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 13.8 μM (MOI = 0.004) and 17.79 μM (MOI = 0.01), CC50 » 50 μM (Vero E6) |
178,232 |
| Fluspirilene (79) | Antipsychotic (diphenylbutylpiperidine) | SARS-CoV: EC50 = 5.96 μM (Vero E6/MA15) MERS-CoV: EC50 = 7.48 μM (Vero E6/Jordan N3) SARS-CoV-2: EC50 = 3.16 μM (MOI = 0.004) and 5.32 μM (MOI = 0.01), CC50 = 30.33 μM (Vero E6) |
178,232 |
| Bazedoxifene (80) | Estrogen receptor modulator | SARS-CoV-2: EC50 = 3.44 μM, CC50 = 14.97 μM (Vero) | 70 |
| Loperamide (81) | Antidiarrheals/μ-opioid receptor agonist | SARS-CoV: EC50 = 5.9 μM, CC50 = 53.8 μM (Vero E6/Frankfurt-1) MERS-CoV: EC50 = 4.8 μM, CC50 = 15.5 μM (Huh-7/EMC/2012) SARS-CoV-2: EC50 = 9.27 μM, CC50 = 29.26 μM (Vero) |
62,70 |
| Cepharanthine (82) | Bis-benzylisoquinoline alkaloids/anti-inflammatory | SARS-CoV-2: EC50 = 4.47 μM, CC50 > 50 μM (Vero) | 70 |
| Berbamine (83) | MERS-CoV: EC50 = 13.14, CC50 > 20 μM (Vero E6) SARS-CoV-2: EC50 = 7.87 μM, CC50 > 50 μM (Vero) |
70,322 | |
| Tetrandrine (84) | MERS-CoV: EC50 = 12.68, CC50 > 20 μM (Vero E6) SARS-CoV-2: EC50 = 3.00 μM, CC50 = 14.92 μM (Vero) |
70,322 | |
| Reserpine (85) | Antihypertensive | SARS-CoV: EC50 = 3.4 μM, CC50 = 25 μM (Vero E6/H.K. strain) | 348 |
| Ivacaftor (86) | Potentiator of CFTR/treat cystic fibrosis | SARS-CoV-2: EC50 = 6.57 μM, CC50 = 12.47 μM (Vero) | 70 |
| ESI-09 (87) | EPAC inhibitor | Resulted in about 2log and 4log reduction in MERS-CoV and SARS-CoV titer in Vero E6 cells, respectively, at 10 μM | 350 |
| Eltrombopag (88) | Thrombopoietin (c-mpl) receptor agonist | SARS-CoV-2: EC50 = 8.27 μM, CC50 > 50 μM (Vero) | 70 |
| Hydroxyprogesterone caproate (89) | Progesterone receptor agonist | SARS-CoV-2: EC50 = 6.30 μM, CC50 > 50 μM (Vero) | 70 |
| Ciclesonide (90) | Corticosteroid/anti-inflammatory/target nsp15 | SARS-CoV-2: EC50 = 4.33 μM, CC50 > 50 μM (Vero) | 70 |
Abbreviations: AAK1, AP2-associated protein kinase 1; CC50, cytotoxic concentration 50%; EC50, half-maximal effective concentration; EPAC, exchange protein directly activated by cAMP; JAK, Janus kinase; MERS-CoV, Middle East respiratory syndrome coronavirus; MOI, multiplicity of infection; mTOR, mammalian target of rapamycin; SARS-CoV, severe acute respiratory syndrome coronavirus; TMPRSS2, transmembrane protease serine 2.