RRC ID 52118
Author Wada Y, Orba Y, Sasaki M, Kobayashi S, Carr MJ, Nobori H, Sato A, Hall WW, Sawa H.
Title Discovery of a novel antiviral agent targeting the nonstructural protein 4 (nsP4) of chikungunya virus.
Journal 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.
Volume 505
Pages 102-112
Published 2017-5
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* Cercopithecus aethiops Chikungunya Fever / drug therapy Chikungunya Fever / virology Chikungunya virus / drug effects* Chikungunya virus / genetics Drug Resistance, Viral / genetics* HEK293 Cells Humans RNA Replicase / antagonists & inhibitors* RNA Replicase / genetics Sequence Alignment Sequence Analysis, RNA Vero Cells Viral Nonstructural Proteins / antagonists & inhibitors* Viral Nonstructural Proteins / genetics Virus Replication / drug effects
IF 3.374
Human and Animal Cells 293T(RCB2202)