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

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-Barre syndrome, 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, prM/M and E) and 7 nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B 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 RNA-dependent RNA polymerase (RdRp) domain. Recently, the high-resolution structure of full-length ZIKV NS5 protein as well as the individual MTase and RdRp 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.