The Zika virus (ZIKV) nonstructural protein 5 (NS5) is the largest enzyme and the most conserved protein of the virus, and plays a critical role in viral replication. NS5 carries two essential enzymatic activities, methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp), which are both promising targets for the development of antiviral compounds. Recently Prof. George F. Gao and Prof. Yi Shi from University of Chinese Academy of Sciences in Beijing and their colleagues solved the crystal structures of NS5 MTase in complex with an RNA cap analogue (m7GpppA) and the free NS5 RdRp from the ZIKV involved in the 2015 outbreak in Brazil.
The article entitled “The crystal structure of Zika virus NS5 reveals conserved drug targets” was published in The EMBO Journal recently (http://emboj.embopress.org/content/early/2017/03/02/embj.201696241).
For the MTase, the GTP‐binding and SAM‐binding pockets are potential targets for antiviral development. For RdRp. The RNA template entry tunnel and the “N pocket” close to the enzyme active site are promising inhibitor binding sites. The authors identified the conserved features of ZIKV NS5 MTase and RdRp structures that could lead to development of current antiviral inhibitors against flaviviruses, including dengue virus and West Nile virus, to treat ZIKV infection. Their results could inform and accelerate the structure-based design of antiviral compounds against ZIKV.
Conserved drug target sites in NS5 protein
This work was supported by the Emergency Task-Force Project of the National Natural Science Foundation of China (NSFC), the Excellent Young Scientist Program from the NSFC and the NSFC Innovative Research Group. This work is also supported by the China Ministry of Science and Technology National 973 Project, the Task-Force of Zika Virus Research from the Chinese Academy of Sciences (CAS), the National Key Plan for Scientific Research and Development of China, Zika Special Project of the Ministry of Science and Technology Reform and Development Project and Strategic Priority Research Program of CAS, the External Cooperation Program of CAS, the Excellent Young Scientist Program of CAS and the Youth Innovation Promotion Association CAS.
