Antivirals against the Chikungunya Virus
Abstract
:1. Introduction
2. CHIKV Replication Cycle
3. Strategies for Identification of Antiviral Compounds
4. Virus Targeting Inhibitors
4.1. Viral Entry and Membrane Fusion
4.2. Capsid Protease
4.3. 6K Protein
4.4. Non-Structural Proteins
4.4.1. Non-Structural Protein 1 (nsP1)
4.4.2. Non-Structural Protein 2 (nsP2)
4.4.3. Non-Structural Protein 3 (nsP3)
4.4.4. Non-Structural Protein 4 (nsP4)
5. Targeting Host Factors
5.1. Viral Entry and Membrane Fusion
5.2. Lipid Pathway Inhibitors
5.3. Pyrimidine and Purine Synthesis Inhibitors
5.4. Protein Synthesis Inhibitors
5.5. Cellular Protein Inhibitors
5.5.1. Cellular Enzyme Inhibitors
Hydrolases
Kinases
Lyases/transferases
5.6. Cellular Receptor Inhibitors
5.6.1. Inhibitors of Channel-Linked Receptors
5.6.2. Inhibitors of Enzyme-linked Receptors
5.7. Immunomodulatory Agents
6. Undefined Targets
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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In Vitro | In Vivo | |||||||
---|---|---|---|---|---|---|---|---|
Compound b | Viral Target c | EC50 (µM) d | CC50 (µM) | SI | Cell Line | Efficacy | Mouse Model | Ref. |
Arbidol * | E2 | 12.2 ± 2.2 | 376 | 36 | MRC5 | ― | ― | [24] |
Suramin * | E2 | 8.8 ± 0.5 | >700 | >39.1 | BHK-21 | Reduced viral burden and decreased foot swelling | C57BL/6 | [25,26,27] |
Picolinic acid | C | 60.63% inhibition with 2 mM | n.s. | n.s. | Vero | ― | ― | [28] |
Amantadine * | 6K | 29.51 | n.s. | n.s. | Vero | ― | ― | [29] |
MADTP (9b) | nsP1 | 1.2 ± 0.009 | 84 ± 19 | 70 | Vero | ― | ― | [30,31,32,33] |
CHVB-032 | nsP1 | 2.7 | >75 | n.s. | Vero | ― | ― | [34,35] |
Lobaric acid | nsP1 | 5.3 ± 0.4 | 50 ± 1.3 | 7 | Huh-7 | ― | ― | [36] |
FHA | nsP1 | 0.12 ± 0.04 | >250 | >1000 | Vero | ― | ― | [37,38] |
FHNA | nsP1 | 0.18 ± 0.11 | >250 | >1000 | Vero | ― | ― | [37,38] |
5-IT | nsP1 | 0.409 | >50 | n.s. | Vero | ― | ― | [39] |
Compound 25 | nsP2 | 3.2 ± 1.8 | 101 ± 50 | 32 | Vero | ― | ― | [40,41,42] |
Compound 8 | nsP2 | 1.5 | >200 | >133.3 | BHK-21 | ― | ― | [43] |
ID1452-2 | nsP2 | 31 | >31 | n.s. | HEK293T | ― | ― | [44] |
Novobiocin * | nsP2 | 20 | n.s. | n.s. | Vero | ― | ― | [45] |
Telmisartan * | nsP2 | 45 | n.s. | n.s. | Vero | ― | ― | [45] |
SRI-43750 | nsP3 | 23 | >40 | n.s. | NHDF | ― | ― | [46] |
Favipiravir * | nsP4 | 25 ± 3 | >636 | n.s. | Vero | decreased mortality by >50% and improved disease outcome | AG129 | [47] |
Reduced viral replication in joints | C57BL/6J | [48] | ||||||
NHC | nsP4 | 0.2 ± 0.1 | 7.7 | n.s. | Vero | ― | ― | [49,50] |
Sofosbuvir * | nsP4 | 2.7 ± 0.5 | 402 ± 3 2 | 149 | Huh-7 | Reduced viremia and joint pain | SwissWebster | [51] |
Compound-A | nsP4 | 0.54 ± 0.08 | 3.70 ± 0.32 | n.s. | Vero | ― | ― | [52] |
In Vitro | In Vivo | |||||||
---|---|---|---|---|---|---|---|---|
Compound b | Suggested Viral Target | EC50 (µM) c | CC50 (µM) | SI | Cell Line | Efficacy | Mouse Model | Ref. |
IIc | E2 | 6.5 ± 1 | 156 | 22 | Vero | ― | ― | [53] |
Bis(benzofuran-thiazolidone)s (3g) | 1.5 | >200 | <133 | Vero | ― | ― | [54] | |
LQM334 | E2 | 81.1 ± 6.4% viral inhibition | n.s. | n.s. | Vero | ― | ― | [55] |
Micafungin * | E1/E2 | 17.2 ± 1.08 | >100 | >5.81 | U2OS | ― | ― | [56] |
Doxycycline * | E2/nsP2 | 15.51 ± 1.62 | n.s. | n.s. | Vero | + ribavirin: Reduction of pathological signs and virus titre | Adult ICR | [57] |
AP4 | C | 10.66 ± 2.25 | 2172 ± 104 | n.s. | Vero | ― | ― | [58] |
EAC | C | 4.01 ± 1.96 | 1657 ± 1109 | n.s. | Vero | ― | ― | [58] |
PSU | C | 22.91 ± 3.83 | 2505 ± 0683 | n.s. | Vero | ― | ― | [58] |
MBZM-N-IBT | nsP2 | 38.68 | >800 | >21 | Vero | ― | ― | [59] |
1,3-thiazolidin-4-one (compound 7) | nsP2 | 0.42 | >100 | n.s. | Vero | ― | ― | [60] |
peptidomimetic 3a | nsP2 | 8.76 | n.s. | n.s. | Vero | ― | ― | [61] |
PEP-I | nsP2 | 34 | Maximum nontoxic dose is 50 µM | n.s. | BHK-21 | ― | ― | [62] |
Nelfinavir * | nsP2 | 14 ± 1 | 22 ± 6 | 1.6 | Vero | ― | ― | [63] |
In Vitro | In Vivo | |||||||
---|---|---|---|---|---|---|---|---|
Compound b | Host Target c | EC50 (µM) d | CC50 (µM) | SI | Cell Line | Efficacy | Mouse Model | Ref. |
Viral Entry and Membrane Fusion | ||||||||
Chloroquine * | pH | 7.0 ± 1.15 | >260 | 37.14 | Vero | ― | ― | [95] |
Obatoclax * | Bcl-2/E1 | 0.03 ± 0.01 | 20.1 ± 4.8 | 670 | BHK-21 | ― | ― | [96] |
Niclosamide * | pH | 0.36 ± 0.08 | >20 | >55.55 | U2OS | ― | ― | [97] |
Nitazoxanide * | pH | 2.96 ± 0.18 | 25 | 8.45 | BHK-21 | ― | ― | [97] |
EIPA | pH ** | Detectable inhibition observed at 0.03 µM | n.s. | n.s. | HSMM | ― | ― | [98] |
Lipid Pathway Inhibitors | ||||||||
Orlistat * | FASN | 0.82 | 8.67 | 10.57 | HEK293T | ― | ― | [99,100,101] |
Cerulenin * | FASN | 3 | 7.57 | 2.53 | HEK293T | ― | ― | [99,100] |
CAY10566 | SCD1 | HEK293T | ― | ― | [100] | |||
TOFA | FASN | 0.15 | >60 | n.s. | HEK293T | Reduction of the viral replication and joint swelling | C57BL/6 | [99] |
Tivozanib * | FLT4 | 0.8 | 8.34 | n.s. | HEK293T | ― | ― | [99] |
Pimozide * | calmodulin | 0.28 | 19.18 | 69.75 | HEK293T | Reduction of the viral replication and joint swelling | C57BL/6 | [99] |
Imipramine * | NPC ** | Detectable inhibition observed at 10 µM | n.s. | n.s. | HFF1 | ― | ― | [102] |
U18666A | NPC ** | Detectable inhibition observed at 0.63 µM | n.s. | n.s. | HFF1 | ― | ― | [102] |
LXR-623 | LXRβ | 2.50 | 63.30 | 25.3 | HFF | ― | ― | [103] |
Pyrimidine and Purine Synthesis Inhibitors | ||||||||
Ribavirin * | IMPDH/ (viral) RdRp ** | 341.1 | >30,000 | 24 | Vero | + doxycycline: Reduction of pathological signs and virus titre | Adult ICR | [57,104] |
Merimepodib * | IMPDH | 1.8 ± 1.0 | 27 ± 3 | n.s. | Vero | ― | ― | [105] |
6-Azauridine | OMP | 0.816 | 208 | 204 | Vero | ― | ― | [104] |
DD363 | DHODH | 3.6 ± 0.6 | 87 ± 7 | n.s. | HEK293T | ― | ― | [106,107] |
RYL-634 | DHODH | 0.26 | >2.5 | >10 | Vero | ― | ― | [108] |
Atovaquone * | DHODH ** | <0.75 | >11.25 | n.s. | Vero | ― | ― | [109] |
Protein Synthesis Inhibitors | ||||||||
Halofuginone | EPRS | 3 log10 viral titer reduction at 100 nM | n.s. | n.s. | HFF | ― | ― | [110] |
Harringtonine | 0.24 | n.s | n.s. | BHK21 | ― | ― | [111] | |
Sorafenib * | FLT4 | 0.16 | n.s. | n.s. | Vero | ― | ― | [99,112] |
Bortezomib * | UPS ** | 0.023 | 0.47 | 20.6 | HeLA | ― | ― | [113] |
SR9009 * | Rev-erb α/β ** | 100-fold reduction in viral titer at 10 µM | n.s. | n.s. | Huh7 | ― | ― | [114] |
Cellular Protein Inhibitors | ||||||||
Sirtinol | SIRT | >2 log10 viral titer reduction at 200 µM | n.s. | n.s. | U2OS | ― | ― | [115] |
Geldanamycin * | HSP90 | 2.5 log10 viral titer reduction at 1.4 µM | >100 | n.s. | HEK293T | ― | ― | [116] |
HS-10 | HSP90 | >2 log10 viral reduction in titre with 6.25 µM | >100 | n.s. | HEK293T | Reduced viral titer, inflammation, and swelling | SVA129 | [116] |
SNX-2112 | HSP90 | >2 log10 viral reduction in titre with 6.25 µM | >100 | n.s. | HEK293T | Reduced viral titer, inflammation, and swelling | SVA129 | [116] |
HA15 | GRP78 | reduction in titre with 25 µM | n.s. | n.s. | Vero | ― | ― | [117] |
16F16 | PDI | 6.6 ± 0.45 | 8.9 ± 9.2 | 1.35 | HEK293T | ― | ― | [118] |
PACMA31 | PDI | 12.1 ± 0.3 | 12.2 ± 9.7 | 1.00 | HEK293T | Less reduction in footbed swelling and viremia than in auranofin group | C57BL/6 | [118] |
Auranofin * | TRX | 1.0 ± 0.13 | 1.6 ± 8.6 | 1.6 | HEK293T | reduced footbed swelling and viremia | C57BL/6 | [118] |
Cellular Enzyme Inhibitors-Hydrolases | ||||||||
Amodiaquine * | Cathepsin B | 18.3 | >50 | >2 | HFF | ― | ― | [119] |
DEAQ | Cathepsin B | 17.3 | >50 | >2.9 | HFF | ― | ― | [119] |
Aristeromycin | SAH | 0.8 | 6.3 | 7.9 | Vero | ― | ― | [120] |
6,6′-Difluoroaristeromycin (2c) | SAH | 0.13 | 1.25 | >9.6 | Vero | ― | ― | [120] |
Cellular Enzyme Inhibitors-Kinases | ||||||||
Dasatinib * | SFK | >10-fold reduction in viral titer at 20 µM | >50 | n.s. | NHDF | ― | ― | [121] |
Torin 1 | mTORC1/2 | >10-fold reduction in viral titer at 1 µM | >1 | n.s. | NHDF | ― | ― | [121] |
CND3514 | PKR ** | 2.2 | >50 | >22.7 | HuH-7 | ― | ― | [122] |
Berberine | MAPK | 1.8 ± 0.5 | >100 | >55.6 | BHK21 | Reduced viremia and disease symptoms | C57BL6/J | [123,124] |
Miltefosine * | Pi3-Akt | antiviral activity was observed at 20–40 µM | n.s. | n.s. | hPDF | ― | ― | [125] |
Prostatin | PCK | 0.2 ± 0.05 | 50 | n.s. | CRL-2522 | ― | ― | [126] |
Bryostatin analogue (4) | PCK | 0.8 ± 0.1 | >50 | n.s. | BGM | [127,128] | ||
Isothiazolo[4,3-b]pyridine (12r) | GAK | antiviral activity was observed <10 µM | n.s. | n.s. | Vero | ― | ― | [129] |
Cellular Enzyme Inhibitors–Lyases/Transferases | ||||||||
DFMO * | ODC1 | 200-fold reduction in viral titer at 500 µM | n.s. | n.s. | BHK-21 | Low reduction in viral titer | C57BL6/J | [130] |
Cellular Receptor Inhibitors–Channel-linked Receptors | ||||||||
Digoxin * | Na+/K+ ATPase | 0.049 | >10 | n.s. | U2OS | ― | ― | [20] |
Lanatoside C * | Na+/K+ ATPase | 38.99% reduction of viral titer with 1 µM | >1 | n.s. | BHK-21 | ― | ― | [131] |
DIDS | CLIC1/4 | 8-fold reduction in viral titer | n.s. | n.s. | HuH-7 | ― | ― | [132] |
9-ACA | CLIC1/4 | 8-fold reduction in viral titer | n.s. | n.s. | HuH-7 | ― | ― | [132] |
NPPB | CLIC1/4 | 18-fold reduction in viral titer | n.s. | n.s. | HuH-7 | ― | ― | [132] |
Cellular Receptor Inhibitors–Enzyme-linked Receptors | ||||||||
5-NT | 5-HT | 2.8 | >5 | n.s. | U2OS | ― | ― | [133,134] |
MM | 5-HT | 97 ± 1.0% viral reduction 10 µM | >10 | n.s. | U2OS | ― | ― | [133] |
Immunomodulatory Agents | ||||||||
Tilorone * | IFN-inducer | 4.2 | 32 | 7.6 | Vero76 | ― | ― | [135] |
C11 | STING | EC90: 16.44 µM | >50 | n.s. | THF | ― | ― | [136] |
G10 | STING | IC90: 8.01 μM | n.s. | n.s. | THF | ― | ― | [137] |
AV-10 | TRIF | IC90: 3.54 μM | n.s. | n.s. | THF | ― | ― | [138] |
Pentosan polysulfate * | IL-10 inducer; decreased proinflammatory cytokines levels | ― | ― | ― | ― | Reduced disease symptoms | C57BL/6 | [139] |
Pixatimod * | HPSE ** | 0.51 ± 0.50 | n.s. | n.s. | Vero | Reduced disease symptoms | C57BL/6 | [140] |
In Vitro | In Vivo | ||||||
---|---|---|---|---|---|---|---|
Compound b | EC50 (µM) c | CC50 (µM) | SI | Cell Line | Efficacy | Mouse Model | Ref. |
Quinolone-N-acylhydrazone (5b) | 1.06 ± 0.08 | 669 ± 4.33 | 631.7 | Vero | ― | ― | [211] |
Thieno[3,2-b]pyrrole (compound 20) | 3-4 | >100 | n.s. | HEK293T | Good in vivo pharmacokinetics | C57BL/6 | [212,213] |
Compound 15 | 42 | n.s. | n.s. | MCF-7 | ― | ― | [214] |
Mefenamic acid * | 13 | >100 | n.s. | Vero | + ribavirin: Reduction of viral titre and hypertrophic effects in liver and spleen | Adult ICR | [167] |
Meclofenamic acid | 18 | >100 | n.s. | Vero | ― | ― | [167] |
Ivermectin * | 0.6 ± 0.1 | 37.9 ± 7.6 | 62.4 | BHK-21 | ― | ― | [123] |
Abamectin * | 1.5 ± 0.6 | 28.2 ± 1.1 | 19.2 | BHK-21 | ― | ― | [123] |
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Battisti, V.; Urban, E.; Langer, T. Antivirals against the Chikungunya Virus. Viruses 2021, 13, 1307. https://doi.org/10.3390/v13071307
Battisti V, Urban E, Langer T. Antivirals against the Chikungunya Virus. Viruses. 2021; 13(7):1307. https://doi.org/10.3390/v13071307
Chicago/Turabian StyleBattisti, Verena, Ernst Urban, and Thierry Langer. 2021. "Antivirals against the Chikungunya Virus" Viruses 13, no. 7: 1307. https://doi.org/10.3390/v13071307