TABLE 2.
Compounds targeting CHIKV replicationa
| Compoundb | Viral target | Resistance mutation(s) |
In vitro efficacy |
In vivo efficacy |
Reference(s) | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| CHIKV strain (genotype)c | EC50 (μM) or other readoutd | CC50 (μM) | Cell line | CHIKV strain (genotype) | Efficacy | Mouse model | ||||
| MADTP-314 (N) (DA) | nsP1 | P34S | IO 899 (ECSA) | 26 ± 11 | >743 | Vero | — | — | — | 53–55 |
| CHVB-032 (N) (DA) | nsP1 | S454G, W456R | IO 899 (ECSA) | 2.7 | >75 | Vero | — | — | — | 56, 57 |
| 6′-β-Fluoro-homoaristeromycin (N, NA) (DA) | nsP1 | G230R, K299E | CHIKV-LS3 | 0.12 ± 0.04 | >250 | VeroE6 | — | — | — | 58, 59 |
| 6′-Fluoro-homoneplanocin A (N, NA) (DA) | nsP1 | G230R, K299E | CHIKV-LS3 | 0.18 ± 0.11 | >250 | VeroE6 | — | — | — | 59 |
| Difluoromethylornithine (R) (HT) | nsP1 | G230R, V326M (nsP1) + *524R (nsP3) | LR06-049 (ECSA) | 3 log10 reduction in titer with 500 μM dose | >500 | BHK-21 | LR06-049 (ECSA) | Modest reduction in CHIKV titers | C57BL/6 | 60, 61, 121 |
| Mycophenolic acid (R) (HT) | nsP1 | S23N, V302M (SINV) | DRDE-06 (ECSA) | 0.21 ± 0.06 | 30 ± 3.1 | Vero | — | — | — | 62, 63, 65 |
| Ribavirin (NA) (HT/DA) | nsP1/nsP4 | (Q21K), S23N, V302M (SINV)/C483Y (CHIKV) | Ross C347 (ECSA) | 341.1 | >30,000 | Vero | — | — | — | 63, 99, 104 |
| Sofosbuvir (NA) (DA) | nsP4 | — | n.s. (Asian) | 2.7 ± 0.5 | 402 ± 32 | Huh-7 | n.s. | Reduced CHIKV-induced edema and viral replication | Swiss Webster mouse arthralgia model | 94 |
| β-d-N4-hydroxycytidine (NA) (DA) | nsP4 | P187S, A189V, I190T (VEEV) | LR2006 OPY1 (ECSA) | 0.2 ± 0.1 | 7.7 | Vero | — | — | — | 95, 96 |
| Favipiravir (NA) (DA) | nsP4 | K291R | IO 899 (ECSA) | 25 ± 3 | >636 | Vero-A | S27 (ECSA) | Reduced mortality by >50% and improved disease outcome | AG129 lethal model | 97 |
| IO 899 (ECSA) | Reduced viral replication in joints and extremities during acute phase | C57BL/6J | 98 | |||||||
| Digoxin (R) (HT) | nsP4 | V209I | SL15649 (ECSA) | 0.048 | >10 | U2OS | — | — | — | 100 |
| HS-10 (HT) | nsP4 | — | Ross (ECSA) | >2 log10 reduction in titer with 6.25 μM dose | >100 | HEK-293T | DMERI09/08 (ECSA) | Reduced inflammation and viremia | SvA129 | 101 |
| SNX-2112 (HT) | nsP4 | — | Ross (ECSA) | >2 log10 reduction in titer with 6.25 μM dose | >100 | HEK-293T | DMERI09/08 (ECSA) | Reduced inflammation and viremia | SvA129 | 101 |
| 6-Azauridine (R) (NA) (HT/DA) | — | — | Ross C347 (ECSA) | 0.8 | 208 | Vero | — | — | — | 104 |
| RYL-634 | — | — | n.s. | 0.26 | >2.5 | Vero | — | — | — | 105 |
| Atovaquone (R) | — | — | LR06-049 (ECSA) | <0.75 | >11.25 | Vero | — | — | — | 106 |
| Berberine | — | — | LR2006 OPY1 (ECSA) | >5 log10 reduction in titer with 3 μM dose | >100 | BHK-21 | LR2006 OPY1 (ECSA) | Reduced inflammation and joint swelling | C57BL/6J | 107, 109 |
| Ivermectin (R) | — | — | LR2006 OPY1 (ECSA) | >4 log10 reduction in titer with 3 μM dose | 37.9 ± 7.6 | BHK-21 | — | — | — | 107 |
| Abamectin (R) | — | — | LR2006 OPY1 (ECSA) | >4 log10 reduction in titer with 3 μM dose | 28.2 ± 1.1 | BHK-21 | — | — | — | 107 |
| Harringtonine | — | — | 0708 (ECSA) | 0.24 | >100 | BHK-21 | — | — | — | 110 |
| Silymarin | — | — | MY/065/08/FN295485 (ECSA) | 35 | 881 | Vero | — | — | — | 111 |
| Andrographolide | — | — | 0708 (ECSA) | 77.39 | 1,098 | HepG2 | — | — | — | 115 |
| Micafungin (R) | — | — | S27 (ECSA) | 20.6 ± 1.7 | >100 | U2OS | — | — | — | 116 |
| MBZM-N-IBT | — | — | S27 (ECSA) | 38.7 | >800 | Vero | — | — | — | 117 |
| Imipramine (R) | — | — | LR2006 OPY1 (ECSA) | 3 log10 reduction in titer with 75 μM dose | >100 | HFF1 | — | — | — | 112 |
| Tomatidine | — | — | LR2006 OPY1 (ECSA) | 1.3 | 156 | Huh-7 | — | — | — | 113 |
| Silvestrol (HT) | — | — | IO 899 (ECSA) | 0.00189 | >0.03 | HEK-293T | — | — | — | 114 |
n.s., not specified; —, not determined/not done (in vivo studies); N, novel; NA, nucleoside analogue; R, repurposed compound; VEEV, Venezuelan equine encephalitis virus. The numbering of mutations that provide resistance is based on the CHIKV genome sequence of the strain indicated in the table, unless indicated otherwise. DA, direct-acting compounds; HT, host-targeting compounds; HT/DA, both host-targeting and direct-acting compounds.
If the study described a family/class of compounds with antiviral activity, only the antiviral activity of the most potent and/or the most representative compound is reported.
Only compounds for which the antiviral activity was tested using infectious CHIKV are included; compounds identified using only replicon/surrogate systems for which confirmatory experiments with infectious CHIKV were lacking were excluded.
Where a compound showed activity in multiple cell lines and against multiple CHIKV strains, the best value (with corresponding cell line) is reported.