寨卡病毒非结构蛋白NS5的结构与功能研究进展

Advance in structure and functions of the nonstructural protein 5 of Zika virus

寨卡病毒(Zika virus,ZIKV)是黄病毒科黄病毒属重要成员,因其能引起小头症、格林-巴利综合征等严重神经疾病引起了全球的关注.NS5蛋白是其基因组编码的最大非结构蛋白,主要包括N端的甲基转移酶MTase(methyltransferase)结构域和C端的RNA依赖的RNA聚合酶RdRp(RNA-dependent RNA polymerase)结构域.NS5蛋白是一个多功能蛋白,不仅负责病毒基因组的复制和加帽过程,而且参与调控宿主的多种天然免疫反应.鉴于其具备重要的生物学功能,NS5蛋白被广泛认为是抗病毒药物设计的重要靶标.近年来,寨卡病毒NS5蛋白的高分辨率结构被成功解析,其生物学功能的研究也取得了重要突破,本文就相关领域的最新进展作一简要综述.

Zika virus(ZIKV)is an important member of genus Flavivirus which includes dengue virus,West Nile virus,Japanese encephalitis virus,and yellow fever virus.ZIKV has attracted worldwide attention because of its unexpected causal link to microcephaly,Guillain-Barrésyndrome,and other serious neurological diseases.So far,it has been spreading to 90 countries or territories worldwide,and approximately 3.6 billion people are now living at risk of ZIKV infection.Although a lot of efforts have been made to understand the pathogenesis of ZIKV,there is no approved vaccines or antiviral drugs available.ZIKV has a single-stranded and positive-sense genome RNA,which contains a single open reading frame flanked by the highly structured untranslated regions(UTRs).The ORF encodes a polyprotein precursor which is further cleaved into 3 structural proteins(C,pr M/M and E)and 7 nonstructural proteins(NS1,NS2 A,NS2 B,NS3,NS4 A,NS4 B and NS5)by either host or viral protease.ZIKV NS5 is the largest and the most conserved protein among all viral proteins.ZIKV NS5 can be divided into two domains:the N-terminal methyltransferase(MTase)domain and C-terminal RNAdependent RNA polymerase(Rd Rp)domain.Recently,the high-resolution structure of full-length ZIKV NS5 protein as well as the individual MTase and Rd Rp domains have been resolved,which led to better understanding of its biological function.As a multifunctional protein,ZIKV NS5 interacts with several cis-acting RNA elements located in the 5′UTR to initiate viral RNA synthesis,and adds the 5′RNA cap structure to facilitate translation of the polyprotein.NS5 is also involved in the regulation of host innate antiviral immune responses.As such,ZIKV NS5 is widely considered to be a potential target for antiviral drug design,and the research towards this goal also accelerated our understanding of its structure and function.A panel of small molecule inhibitors targeting ZIKV NS5 has been identified to have ideal antiviral effects in both cell cultures and animal models.This review summarizes recent advances on the structure and biological functions of ZIKV NS5 protein.