Discovery of a novel antiviral agent targeting the nonstructural protein 4 (nsP4) of chikungunya virus.
Discovery of a novel antiviral agent targeting the nonstructural protein 4 (nsP4) of chikungunya virus.
复制标题
发现一种针对基孔肯雅病毒非结构蛋白 4 (nsP4) 的新型抗病毒药物。
DOI：
10.1016/j.virol.2017.02.014
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Sawa H
中科院分区：
文献类型：
--
作者：
Wada Y;Orba Y;Sasaki M;Kobayashi S;Carr MJ;Nobori H;Sato A;Hall WW;Sawa H
基孔肯雅热（CHIKF）是由基孔肯雅病毒（CHIKV）感染引起的，基孔肯雅病毒是一种再次出现的蚊媒人畜共患病。目前，还没有批准的治疗CHIKF的药物。在此，我们研究了抑制CHIKV感染的候选化合物。对化合物文库进行筛选，发现一个候选化合物，即与苯并咪唑相关的化合物化合物- a，在纳摩尔浓度下可抑制几种CHIKV毒株和Sindbis病毒株的感染。为了研究其抑制作用机制，分离出一株化合物- a耐药的CHIKV (res-CHIKV)，并通过含有res-CHIKV中氨基酸取代的反向基因重组CHIKV鉴定出与耐药相关的关键突变。这些结果表明，化合物a的靶点是位于rna依赖rna聚合酶（RdRp）功能域之一的非结构蛋白4 （nsP4）中的M2295残基。我们还通过CHIKV复制子证实了化合物a抑制了CHIKV的RdRp功能。
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.