Table 3.
Small-molecule SARS-CoV-2 inhibitors targeting host cell proteins.
| Number of chemical structures in Fig. | Inhibitor | Testing model | Activity IC50 (μmol/L) | Toxicity CC50 (μmol/L) | Clinical information | Ref. |
|---|---|---|---|---|---|---|
| Target ACE2 | ||||||
| Fig. 7 (64) | Candesartan | In vitro | – | – | Preclinical | 160 |
| Fig. 7 (65) | Olmesartan | In vitro | – | – | Preclinical | 159 |
| Fig. 7 (66) | Telmisartan | – | – | – | Phase 3 NCT04356495 |
|
| Fig. 7 (67) | Losartan | – | – | – | Phase 1 (NCT04312009, NCT04311177, NCT04328012, NCT04335123) | 162, 163, 164 |
| Target TMPRSS2 | ||||||
| Fig. 8 (68) | Camostat mesylate | In vitro (pseudovirus) | ~1 | ≥500 | Phase 2a/4 (NCT04321096, NCT04338906) | 10 |
| Fig. 8 (69) | Nafamostat | In vitro | 22.50 | ≥100 | NCT04352400 | 19 |
| 0.01 | – | 177 | ||||
| Fig. 8 (70) | MI-432 | In vitro | ≤10 | ≥50 | Preclinical | 180 |
| Fig. 8 (71) | MI-1900 | In vitro | ≤50 | ≥50 | Preclinical | 180 |
| Target cathepsin B/L | ||||||
| Fig. 9 (72) | Amantadine | In vitro | ≥100 | ≥100 | Preclinical | 187 |
| Fig. 9 (73) | Chlorpromazine | In vitro | ≥100 | ≥100 | Preclinical | 187 |
| Fig. 9 (74) | E64-d | In vitro | ~4.487 | ≥0 | Preclinical | 187 |
| Fig. 9 (75) | Chloroquine | In vitro | 2.71 | 273.20 | Several clinical trials (ChiCTR2000029609 et al.) | 97,188,189 |
| In vitro | 2.01 | >30 | 212 | |||
| Fig. 9 (76) | Hydroxychloroquine | In vivo (macaques) | 4.51 | 249.50 | Several clinical trials (ChiCTR2000029803, ChiCTR2000029868, ChiCTR2000029898, ChiCTR2000029899, ChiCTR2000029992, ChiCTR2000030054, NCT04315948) | 124,146,188,189,191 |
| In vitro | 4.47 | >30 | 212 | |||
| Fig. 9 (77) | Apilimod | In vitro | 0.023 | – | Preclinical | 68 |
| In vitro | ~0.01 | – | Preclinical | 197 | ||
| Fig. 9 (78) | MDL-28170 | In vitro | 0.22 | – | Preclinical | 68 |
| Fig. 9 (79) | Z LVG CHN2 | In vitro | 0.19 | – | Preclinical | 68 |
| Fig. 9 (80) | VBY-825 | In vitro | 0.3 | – | Preclinical | 68 |
| Fig. 9 (81) | ONO 5334 | In vitro | 0.41 | – | Preclinical | 68 |
| Fig. 9 (82) | Teicoplanin | In vitro | 1.66 | – | Preclinical | 201 |
| Fig. 9 (83) | Omeprazole | In vitro | 17.06 | ≥40 | Preclinical | 146 |
| Dual inhibitors: Target cathepsin L and 3CLpro | ||||||
| Fig. 5 (29) | Calpain inhibitors II | In vitro | 2.07 ± 0.76 | ≥100 | Preclinical | 86,88 |
| Fig. 5 (30) | Calpain inhibitors XII | In vitro | 0.49 ± 0.18 | ≥100 | Preclinical | 86,88 |
| Other small-molecule inhibitor | ||||||
| Fig. 10 (84) | Thalidomide | – | – | – | Phase 2 (NCT04273581, NCT04273529) | 205 |
| Fig. 10 (85) | Fingolimod | – | – | – | NCT04280588 | 205,207 |
| Fig. 10 (86) | Teriflunomide | In vitro | 6 | – | Small patient cohort | 208 |
| In vitro | 26.06 | 850.5 | 210 | |||
| Fig. 10 (87) | Leflunomide | In vitro | 41.49 | 879.0 | Preclinical | 210 |
| Fig. 10 (88) | Brequinar | In vitro | 0.123 | 231.3 | Preclinical | 210 |
| Fig. 10 (89) | S312 | In vitro | 1.56 | 158.2 | Preclinical | 210 |
| Fig. 10 (90) | S416 | In vitro | 0.017 | 178.6 | Preclinical | 210 |
| Fig. 10 (91) | ROC-325 | In vitro | 3.28 ± 0.57 | >30 | Preclinical | 212 |
| Fig. 10 (92) | Clomipramine | In vitro | 13.6 ± 2.96 | >30 | Preclinical | 212 |
| Fig. 10 (93) | Hycanthone | In vitro | 5.79 ± 0.26 | 14.2 | Preclinical | 212 |
| Fig. 10 (94) | Mefloquine | In vitro | 3.85 ± 0.24 | 8.78 | Preclinical | 212 |
| In vitro | 8.06 | 18.53 | Preclinical | 244 | ||
| In vivo | 3.2 | ≥10 | Preclinical | 94 | ||
| Fig. 10 (95) | Dithioerythritol thiosulfonate 16 | In vitro | 50 | ≥500 | Preclinical | 214 |
| GNS561 | In vitro | 0.006 for USA-WA1/2020; 0.03 for IHU MI6 | 2.0 for USA-WA1/2020; 6.7 for IHU MI6 | Preclinical | 215 | |
| Fig. 10 (96) | VPS34-IN1 | In vitro | 0.55 | ≥50 | Preclinical | 218 |
| Fig. 10 (97) | PIK-III | In vitro | 0.12 | ≥50 | Preclinical | 218 |
| Fig. 10 (98) | Orlistat | In vitro | 21.25 | ≥1000 | Preclinical | 218 |
| Fig. 10 (99) | Triacsin C | In vitro | 0.04 | ≥50 | Preclinical | 218 |
| Fig. 10 (100) | MI-1851 | In vitro | ≤10 | ≥50 | Preclinical | 180 |
| Fig. 10 (101) | Decanoyl-RVKR-chloromethylketone (dec-RVKR-cmk) | In vitro | 0.057 | 318.2 | Preclinical | 221 |
| Fig. 10 (102) | Homoharringtonine | In vitro | 2.55 | 59.75 | Preclinical | 99 |
| Fig. 10 (103) | Emetine | In vitro | 0.46 | 56.46 | Preclinical | 99 |
| In vitro | 0.0004 | >10 | Preclinical | 94 | ||
| Fig. 10 (104) | 2-Deoxy-d-glucose (2-DG) | In vitro | 9090 | – | Preclinical | 228,229 |
| Fig. 10 (105) | Pladienolide B | In vitro | 0.007 | – | Preclinical | 228 |
| Fig. 10 (106) | Ribavirin | In vitro | 70 | – | NCT04356677 | 228 |
| Fig. 10 (107) | NMS-873 | In vitro | 0.025 | – | Preclinical | 140,228 |
| Fig. 10 (108) | Cycloheximide | In vitro | 0.17 | – | Preclinical | 228 |
| Fig. 10 (109) | Baricitinib | – | – | – | Phase 2,3,4 (2020-001854-23, 2020-001354-22, NCT04358614) | 232 |
| Fig. 10 (110) | Nitazoxanide | In vitro | 2.12 | >35.53 | Phase 2, 3 (NCT04341493, NCT01056380, NCT04348409) | 19,238 |
| In vitro | 4.90 | >300 | 237 | |||
| Fig. 10 (111) | JIB-04 | In vitro | 0.695 | >300 | Preclinical | 237 |
| Fig. 10 (112) | Fenofibrate | In vitro | 20 | >100 | Preclinical | 187 |
| Fig. 10 (113) | Plitidepsin | In vitro | 0.70 nmol/L for Vero E6; 0.73 nmol/L for hACE2-293 T; 1.62 nmol/L for human lung cells | 1.99 nmol/L in Vero E6; ≥200 nmol/L for hACE2-293 T; 65.43 nmol/L for human lung cells | Phase 1/2 (NCT04382066) | 187,239 |
| Fig. 10 (114) | Clemizole hydrochloride | In vitro | 23.94 | ≥40 | Preclinical | 146 |
| Fig. 10 (115) | Benztropine mesylate | In vitro | 17.79 | >>50 | Preclinical | 244 |
| In vitro | 1.8 | – | Preclinical | 78 | ||
| Fig. 10 (116) | Fluphenazine dihydrochloride | In vitro | 8.98 | 20.02 | Preclinical | 244 |
| Fig. 10 (117) | Amodiaquine hydrochloride | In vitro | 5.64 | >38.63 | Preclinical | 244 |
| Fig. 10 (118) | Amodiaquine dihydrochloride dihydrate | In vitro | 4.94 | 34.42 | Preclinical | 244 |
| Fig. 10 (119) | Thiethylperazine maleate | In vitro | 8.02 | 18.37 | Preclinical | 244 |
| Fig. 10 (120) | Triparanol | In vitro | 6.41 | 21.21 | Preclinical | 244 |
| Fig. 10 (121) | Terconazole | In vitro | 16.14 | 41.46 | Preclinical | 244 |
| Fig. 10 (122) | Fluspirilene | In vitro | 5.32 | 30.33 | Preclinical | 244 |
| Fig. 10 (123) | Clomipramine hydrochloride | In vitro | 7.59 | >29.68 | Preclinical | 244 |
| Fig. 10 (124) | Promethazine hydrochloride | In vitro | 10.44 | >42.59 | Preclinical | 244 |
| Fig. 10 (125) | Toremifene citrate | In vitro | 11.3 | 20.51 | Preclinical | 244 |
| Fig. 10 (126) | Tamoxifen citrate | In vitro | 8.98 | 37.96 | Preclinical | 244 |
| Fig. 10 (127) | Imatinib mesylate | In vitro | 5.32 | >30.86 | Preclinical | 244 |
| In vivo (humanized mice carrying hPSC-derived lung xenografts) | 2.15 | – | Preclinical | 27 | ||
| Fig. 10 (128) | Bruceine A | In vitro | 0.011 | 31.4 | Preclinical | 246 |
| Fig. 10 (129) | Bufalin | In vitro | 0.018 | >40 | Preclinical | 246 |
| Fig. 10 (130) | Cinobufagin | In vitro | 0.018 | >40 | Preclinical | 246 |
| Fig. 10 (131) | Bufotaline | In vitro | 0.0259 | >40 | Preclinical | 246 |
| Fig. 10 (132) | Periplocoside | In vitro | 0.0657 | >40 | Preclinical | 246 |
| Fig. 10 (133) | Brusatol | In vitro | 0.0492 | 19 | Preclinical | 246 |
| Fig. 10 (134) | Digoxin | In vitro | 0.1541 | >40 | Preclinical | 246 |
| Fig. 10 (135) | Veratridine | In vitro | 2.376 | >100 | Preclinical | 246 |
| Fig. 10 (136) | Oridonin | In vitro | 1.462 | >40 | Preclinical | 246 |
| Fig. 10 (137) | Isoalantolactone | In vitro | 1.483 | >40 | Preclinical | 246 |
| Fig. 10 (138) | Isoliensinine | In vitro | 1.615 | 40 | Preclinical | 246 |
| Fig. 10 (139) | Alantolactone | In vitro | 1.724 | 36.7 | Preclinical | 246 |
| Fig. 10 (140) | Cryptotanshinone | In vitro | 5.024 | >100 | Preclinical | 246 |
| Fig. 10 (141) | Dehydrocostus lactone | In vitro | 2.322 | 36.2 | Preclinical | 246 |
| Fig. 10 (142) | Momordinic | In vitro | 3.529 | >40 | Preclinical | 246 |
| Fig. 10 (143) | Liensinine | In vitro | 2.537 | 25.4 | Preclinical | 246 |
| Fig. 10 (144) | Dehydrodiisoeugenol | In vitro | 10.29 | ≥100 | Preclinical | 246 |
| Fig. 10 (145) | Cornuside | In vitro | 5.262 | ≥40 | Preclinical | 246 |
| Fig. 10 (146) | Roburicacid | In vitro | 5.267 | ≥40 | Preclinical | 246 |
| Fig. 10 (147) | Coniferylaldehyde | In vitro | 11.03 | ≥40 | Preclinical | 246 |
| Fig. 10 (148) | Panduratin A | In vitro | 0.81 | 14.71 | Preclinical | 247 |
| Fig. 10 (149) | Thioguanine | In vitro | 1.7 | 25.4 | Preclinical | 94 |
| Fig. 10 (150) | Moxidectin | In vitro | 3.1 | 6.9 | Preclinical | 94 |
| Fig. 10 (151) | Ivacaftor | In vitro | 3.7 | 12.9 | Preclinical | 94 |
| Fig. 10 (152) | Azelnidipine | In vitro | 5.3 | 12.9 | Preclinical | 94 |
| Fig. 10 (153) | Penfluridol | In vitro | 2.4 | 12.9 | Preclinical | 94 |
| Fig. 10 (154) | Salinomycin | In vitro | 0.00048 | 13.1 | Preclinical | 94 |
| Fig. 10 (155) | Monensin | In vitro | 6.4 | 6.6 | Preclinical | 94 |
| Fig. 10 (156) | Maduramicin | In vitro | 1.3 | 3.4 | Preclinical | 94 |
| Fig. 10 (157) | Tilorone | In vitro | 0.18 | – | Preclinical | 248 |
| Fig. 10 (158) | Pyronaridine | In vitro | 0.198 | – | Preclinical | 248 |
| Fig. 10 (159) | Mycophenolic acid | In vivo (humanized mice carrying hPSC-derived lung xenografts) | 0.9 | – | Preclinical | 27 |
| Fig. 10 (160) | Quinacrine dihydrochloride | In vivo (humanized mice carrying hPSC-derived lung xenografts) | 0.84 | – | Preclinical | 27 |