Development of Small-Molecule MERS-CoV Inhibitors
Abstract
:1. Introduction
2. MERS-CoV Life Cycle and Potential Targets for the Development of Small-Molecule Inhibitors Against MERS-CoV Infection
3. Current Small-Molecule Inhibitors Against MERS-CoV Infection and Their Mechanisms of Action
3.1. MERS-CoV Entry Inhibitors
3.2. MERS-CoV Replication Inhibitors
3.2.1. MERS-CoV Inhibitors Targeting Papain-Like Protease
3.2.2. MERS-CoV Inhibitors Targeting 3C-Like Protease
3.3. Other Small-Molecule Inhibitors with Defined or Undefined Mechanisms of Action
4. Strategies for Developing Small-Molecule MERS-CoV Inhibitors
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Compound | Sequence | Testing Model | Cell Lines Tested | EC50 (μM) | CC50 (μM) | Ref. |
---|---|---|---|---|---|---|
Peptide inhibitors disturbing membrane fusion | ||||||
HR2P | SLTQINTTLLDLTYEMLSLQQVVKALNESYIDLKEL | In vitro | Vero cells Huh-7 cells | 0.6 0.93 ± 0.15 b | >1000 | [16] |
HR2P-M2 | SLTQINTTLLDLEYEMKKLEEVVKKLEESYIDLKEL | In vitro; in vivo: hDPP4 Tg mice | Calu-3 and Vero cells; Ad5-hDPP4 mice | 0.55 ± 0.04 b | - | [16,18,19] |
P21S10 | LDLTYEM LSLQQVV K*LNE*Y | In vitro | Huh-7 cells | 0.97 ± 0.08; 0.33 ± 0.04 b | >100 | [20] |
P21S2 | L*LTY*M LSLQQVV KALNESY | In vitro | Huh-7 cells | 3.90 ± 1.1 b | - | [20] |
P21S4 | LDLT*EM L*LQQVV KALNESY | In vitro | Huh-7 cells | 7.14 ± 0.7 b | - | [20] |
P21S5 | LDLTYEM *SLQ*VV KALNESY | In vitro | Huh-7 cells | 10.7 ± 2.6 b | - | [20] |
P21S8 | LDLTYEM LSLQ*VV K*LNESY | In vitro | Huh-7 cells | 3.03 ± 0.29; 0.26 ± 0.05 b | >100 | [20] |
P21S9 | LDLTYEM LSLQQVV *ALN*SY | In vitro | Huh-7 cells | 14.1 ± 2.3 b | - | [20] |
P21L2 | LXLTYXM LSLQQVV KALNESY | In vitro | Huh-7 cells | 10.9 ± 1.1 b | - | [20] |
P21L4 | LDLTXEM LXLQQVV KALNESY | In vitro | Huh-7 cells | 8.21 ± 0.9 b | - | [20] |
P21L5 | LDLTYEM XSLQXVV KALNESY | In vitro | Huh-7 cells | 4.49 ± 0.6 b | - | [20] |
P21L8 | LDLTYEM LSLQXVV KXLNESY | In vitro | Huh-7 cells | 20.6 ± 3.3 b | - | [20] |
P21L9 | LDLTYEM LSLQQVV XALNXSY | In vitro | Huh-7 cells | 10.9 ± 1.0 b | - | [20] |
P21L10 | LDLTYEM LSLQQVV KXLNEXY | In vitro | Huh-7 cells | 3.55 ± 0.2 b | - | [20] |
P21R8 | LDLTYEM LSLQ^VV K^LNESY | In vitro | Huh-7 cells | 16.3 ± 1.1 b | - | [20] |
P21S8Z | LDLTYEZ LSLQ*VV K*LNESY | In vitro | Huh-7 cells | 2.80 ± 0.74; 0.63 ± 0.05 b | >100 | [20] |
P21S8F | LDLTYEM LSLQ*VV K*LNESF | In vitro | Huh-7 cells | 2.16 ± 1.1 b | - | [20] |
P21S8ZF | LDLTYES LSLQ*VV K*LNESF | In vitro | Huh-7 cells | 3.89 ± 0.8 b | - | [20] |
P9 a | NGAICWGPCPTAFRQIGNCGHFKVRCCKIR | In vitro | MDCK cells | 5.00 μg/mL | 380 μg/mL | [21] |
LLS | LEELSKKLEELSKKLEELSKKLEELSKKLEELSKK-βA-K (C16) | In vitro | Huh-7 cells | 0.24 ± 0.08 b | 4.04 ± 0.4 | [22] |
IIS | IEEISKKIEEISKKIEEISKKIEEISKKIEEISKK-βA-K (C16) | In vitro | Huh-7 cells | 0.10 ± 0.02 b | 88.8 ± 28 | [22] |
AAS | AEEASKKAEEASKKAEEASKKAEEASKKAEEASKK-βA-K(C16) | In vitro | Huh-7 cells | 4.47 ± 1.7 b | 2.38 ± 0.9 | [22] |
FFS | FEEFSKKFEEFSKKFEEFSKKFEEFSKKFEEFSKK-βA-K (C16) | In vitro | Huh-7 cells | 3.11 ± 0.9 b | >100 | [22] |
YYS | YEEYSKKYEEYSKKYEEYSKKYEEYSKKYEEYSKK-βA-K(C16) | In vitro | Huh-7 cells | 6.26 ± 2.1 b | 19.8 ± 1.6 | [22] |
IIY | IEEIYKKIEEIYKKIEEIYKKIEEIYKKIEEIYKK-βA-K (C16) | In vitro | Huh-7 cells | 0.52 ± 0.4 b | >100 | [22] |
IIW | IEEIWKKIEEIWKKIEEIWKKIEEIWKKIEEIWKK-βA-K (C16) | In vitro | Huh-7 cells | 10.6 ± 2.4 b | >100 | [22] |
IIH | IEEIHKKIEEIHKKIEEIHKKIEEIHKKIEEIHKK-βA-K (C16) | In vitro | Huh-7 cells | 1.68 ± 0.47 b | >100 | [22] |
IIQ | IEEIQKKIEEIQKKIEEIQKKIEEIQKKIEEIQKK-βA-K (C16) | In vitro | Huh-7 cells | 0.13 ± 0.1; 0.11 ± 0.02 b | >100 | [22] |
IIK | IEEIKKKIEEIKKKIEEIKKKIEEIKKKIEEIKKK-βA-K (C16) | In vitro | Huh-7 cells | 0.45 ± 0.13 b | 4.54 ± 0.6 | [22] |
IIE | IEEIEKKIEEIEKKIEEIEKKIEEIEKKIEEIEKK-βA-K (C16) | In vitro | Huh-7 cells | 2.93 ± 0.95 b | >100 | [22] |
Inhibitor | Testing Model | Cell Lines | EC50 (μM) | CC50 (μM) | Ref. |
---|---|---|---|---|---|
Inhibitors blocking the binding between virus and host cells | |||||
ADS-J1 | In vitro | NBL-7 and Huh-7 cells | 0.6 | 26.9 | [27] |
Inhibitors disrupting endocytosis | |||||
Chlorpromazine | In vitro | Huh-7 cells | 23.33 ± 2.89 a; 49 ± 1.2; 9.514 | >40; 21.3 ± 1.0 | [5,6,7,26] |
Promethazine | In vitro | Huh-7 cells | 16.67 ± 7.22 a; 11.802 | >40 | [7,26] |
Fluphenazine | In vitro | Huh-7 cells | 15.00 ± 4.33 a; 5.868 | ~40 | [7,26] |
K11777 | In vitro | Vero cells | 0.046 | >10 | [32] |
Camostat | In vitro | Vero-TMPRSS2 cells | ~1 | - | [31] |
Ouabain | In vitro | Huh-7 cells | ~0.05 | - | [35] |
Bufalin | In vitro | Huh-7 cells | 0.01–0.015 | - | [35] |
Dihydrotanshinone | In vitro | - | 0.5–1 μg/mL | - | [36] |
Inhibitors interrupting MERS-CoV MERS-CoV RNA replication and translation | |||||
Disulfiram | In vitro | - | 22.7 ± 0.5 | - | [47] |
3k | In vitro | - | 5.8 ± 1.6 | - | [48] |
3h | In vitro | - | 7.3 ± 2.1 | - | [48] |
3i | In vitro | - | 7.4 ± 2.2 | - | [48] |
CE-5 | In vitro | HEK293T cells | ~12.5 | - | [53] |
6b | In vitro | Huh-7 cells | 1.4 ± 0.0 | >100 | [54] |
6c | In vitro | Huh-7 cells | 1.2 ± 0.6 | >100 | [54] |
6d | In vitro | Huh-7 cells | 0.6 ± 0.0 | 58.6 ± 1.2 | [54] |
GC376 | In vitro | - | 1.56 ± 0.09; 0.9 | >150 | [52,55] |
GC813 | In vitro | - | 0.5 | - | [52] |
10a | In vitro | Vero81 cells | 0.5 | >100 | [52] |
10c | In vitro | Vero81 cells | 0.8 | >100 | [52] |
N3 | In vitro | - | 0.28 ± 0.02 | - | [56] |
Inhibitors with undefined mechanisms | |||||
Silvestrol | In vitro | MRC-5 cells | 0.0013 | 0.4 | [57] |
GS-5734 | In vitro | HAE cells | 0.074 ± 0.023 | >10 | [58] |
GS-441524 | In vitro | HAE cells | 0.86 ± 0.78 | >100 | [58] |
Chloroquine | In vitro | MDMs and MDDCs cells | 3.0 ± 1.1; 6.275 | 58.1 ± 1.1 | [7,59] |
Emetine dihydrochloride hydrate | In vitro | Vero E6 cells | 0.014 | - | [7] |
Hydroxychloroquine sulfate | In vitro | Vero E6 cells | 8.279 | - | [7] |
Mefloquine | In vitro | Vero E6 cells | 7.416 | - | [7] |
Amodiaquine dihydrochloride dehydrate | In vitro | Vero E6 cells | 6.212 | - | [7] |
E-64-D | In vitro | Vero E6 cells | 1.275 | - | [7] |
Gemcitabine hydrochloride | In vitro | Vero E6 cells | 1.216 | - | [7] |
Tamoxifen citrate | In vitro | Vero E6 cells | 10.117 | - | [7] |
Toremifene citrate | In vitro | Vero E6 cells | 12.915 | - | [7] |
Terconazole | In vitro | Vero E6 cells | 12.203 | - | [7] |
Triparanol | In vitro | Vero E6 cells | 5.283 | - | [7] |
Anisomycin | In vitro | Vero E6 cells | 0.003 | - | [7] |
Cycloheximide | In vitro | Vero E6 cells | 0.189 | - | [7] |
Homoharringtonine | In vitro | Vero E6 cells | 0.0718 | - | [7] |
Benztropine mesylate | In vitro | Vero E6 cells | 16.627 | - | [7] |
Fluspirilene | In vitro | Vero E6 cells | 7.477 | - | [7] |
Thiothixene | In vitro | Vero E6 cells | 9.297 | - | [7] |
Astemizole | In vitro | Vero E6 cells | 4.884 | - | [7] |
Chlorphenoxamine hydrochloride | In vitro | Vero E6 cells | 12.646 | [7] | |
Thiethylperazine maleate | In vitro | Vero E6 cells | 7.865 | - | [7] |
Triflupromazine hydrochloride | In vitro | Vero E6 cells | 5.758 | - | [7] |
Clomipramine hydrochloride | In vitro | Vero E6 cells | 9.332 | - | [7] |
Imatinib mesylate | In vitro | Vero E6 cells | 17.689 | - | [7] |
Dasatinib | In vitro | Vero E6 cells | 5.468 | - | [7] |
Loperamide | In vitro | Vero E6 cells | 4.8 ± 1.5 | 15.5 ± 1.0 | [7] |
Lopinavir | In vitro | Vero E6 cells | 8.0 ± 1.5 | 24.4 ± 1.0 | [7] |
SSYA10-001 | In vitro | Vero E6 cells | ~25 | >500 | [60] |
ESI-09 | In vitro | Calu-3 and Vero E6 cells | 5–10 | >50 | [61] |
Mycophenolic acid | In vitro | Vero E6 cells | 2.87 | - | [60] |
BCX4430 | In vitro | - | 68.4 | >100 | [62] |
Fleximer analogues 2 | In vitro | Vero cells Huh-7 cells | 23 ± 0.6; 27 ± 0.0 | 71 ± 14; 149 ± 6.8 | [63] |
Nutlin-3 | In vitro | Huh-7 cells | 6.9 ± 1.4 | 26.8 ± 1.6 | [64] |
Amodiaquine dihydrochloride | In vitro | Huh-7 cells | 2.1 ± 0.7 | 12.3 ± 5.9 | [64] |
Saracatinib | In vitro | Huh-7 cells | 2.9 ± 0.6 | 57 ± 5.5 | [64] |
Sotrastaurin | In vitro | Huh-7 cells | 9.7 ± 3.3 | >50 | [64] |
Acetophenazine maleate | In vitro | Huh-7 cells | 11.2 ± 5.0 | 23.6 ± 3.8 | [64] |
Dosulepin hydrochloride | In vitro | Huh-7 cells | 3.4 ± 0.0 | 28.9 ± 0.0 | [64] |
Methotrimeprazine maleate salt | In vitro | Huh-7 cells | 2.5 ± 0.0 | 24.5 ± 0.0 | [64] |
N1-(4-pyridyl)-2-chloro-5-nitrobenzamide | In vitro | Huh-7 cells | 10.5 ± 0.3 | >50 | [64] |
FA-613 | In vitro | Huh-7 cells | 10.2 ± 0.2 | - | [65] |
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Share and Cite
Liang, R.; Wang, L.; Zhang, N.; Deng, X.; Su, M.; Su, Y.; Hu, L.; He, C.; Ying, T.; Jiang, S.; et al. Development of Small-Molecule MERS-CoV Inhibitors. Viruses 2018, 10, 721. https://doi.org/10.3390/v10120721
Liang R, Wang L, Zhang N, Deng X, Su M, Su Y, Hu L, He C, Ying T, Jiang S, et al. Development of Small-Molecule MERS-CoV Inhibitors. Viruses. 2018; 10(12):721. https://doi.org/10.3390/v10120721
Chicago/Turabian StyleLiang, Ruiying, Lili Wang, Naru Zhang, Xiaoqian Deng, Meng Su, Yudan Su, Lanfang Hu, Chen He, Tianlei Ying, Shibo Jiang, and et al. 2018. "Development of Small-Molecule MERS-CoV Inhibitors" Viruses 10, no. 12: 721. https://doi.org/10.3390/v10120721