| RRC ID |
52118
|
| 著者 |
Wada Y, Orba Y, Sasaki M, Kobayashi S, Carr MJ, Nobori H, Sato A, Hall WW, Sawa H.
|
| タイトル |
Discovery of a novel antiviral agent targeting the nonstructural protein 4 (nsP4) of chikungunya virus.
|
| ジャーナル |
Virology
|
| Abstract |
Chikungunya fever (CHIKF) is caused by chikungunya virus (CHIKV) infection which is a re-emerging mosquito-borne zoonosis. At present, there are no approved therapeutics for CHIKF. Herein, we have investigated candidate compounds which can inhibit CHIKV infection. Screening of chemical compound libraries were performed and one candidate, a benzimidazole-related compound designated Compound-A was found to inhibit infection by several CHIKV strains and a Sindbis virus strain at nanomolar concentrations. To investigate the inhibitory mechanism of action, a Compound-A resistant CHIKV (res-CHIKV) was isolated and a key mutation associated with resistance was identified by reverse-genetic recombinant CHIKVs containing amino acid substitutions present in res-CHIKV. These results demonstrated that the target site of Compound-A was the M2295 residue in the nonstructural protein 4 (nsP4), which is located in one of the functional domains of RNA-dependent RNA-polymerase (RdRp). We also confirmed that Compound-A inhibits RdRp function of CHIKV by using CHIKV replicons.
|
| 巻・号 |
505
|
| ページ |
102-112
|
| 公開日 |
2017-5-1
|
| DOI |
10.1016/j.virol.2017.02.014
|
| PII |
S0042-6822(17)30055-7
|
| PMID |
28236746
|
| MeSH |
Amino Acid Sequence
Amino Acid Substitution / genetics
Animals
Antiviral Agents / pharmacology*
Base Sequence
Benzimidazoles / pharmacology*
Chikungunya Fever / drug therapy
Chikungunya Fever / virology
Chikungunya virus / drug effects*
Chikungunya virus / genetics
Chlorocebus aethiops
Drug Resistance, Viral / genetics*
HEK293 Cells
Humans
RNA-Dependent RNA Polymerase / antagonists & inhibitors*
RNA-Dependent RNA Polymerase / genetics
Sequence Alignment
Sequence Analysis, RNA
Vero Cells
Viral Nonstructural Proteins / antagonists & inhibitors*
Viral Nonstructural Proteins / genetics
Virus Replication / drug effects
|
| IF |
2.819
|
| 引用数 |
14
|
| リソース情報 |
| ヒト・動物細胞 |
293T(RCB2202) |
