Volume 26, No 11, Nov 2016
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 26 Issue 11, November 2016: 1260-1263
LETTERS TO THE EDITOR
Mechanisms of activation and inhibition of Zika virus NS2B-NS3 protease
Xia Chen1,2,*, Kailin Yang3,*, Chen Wu1,*, Cheng Chen1, Can Hu1,2, Olga Buzovetsky4, Zefang Wang1, Xiaoyun Ji5, Yong Xiong4 and Haitao Yang1,2
1School of Life Sciences, Tianjin University, Tianjin 300072, China
2Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457, China
3Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
4Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA
5The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China
Correspondence: yanght@tju.edu.cn; Xiaoyun Ji, Tel: +86-25-89684060,xiaoyun.ji@nju.edu.cn
Since ZIKV outbreak was first reported in South and Central America and the Caribbean, it has spread to both North America and Asia1. Preliminary reports have now estimated as many as 1.3 million cases of infection in this widespread epidemic2. Initially it was thought that the ZIKV only causes mild symptoms such as fever, myalgia, and rash; recent studies have revealed that ZIKV can also cause severe neurological pathologies such as neonatal microcephaly and Guillain-Barre syndrome3. In response to the spreading epidemic of ZIKV infection, the World Health Organization has declared a Public Health Emergency of International Concern4. ZIKV is a mosquito-borne flavivirus, whose NS3 protease (NS3pro) is required for proteolytic processing of its polyprotein to enable viral replication5, thus making NS3pro an attractive therapeutic target for inhibiting viral proliferation. In the past, successful structure-based drug development against NS3pro of the hepatitis C virus (HCV) has generated a series of United States Food and Drug Administration (FDA)-approved inhibitors with potent efficacy for viral eradication6. Flavivirus NS3pro exists predominantly in an inactive state; however, upon association with the NS2B viral protein, its enzymatic activity increases by 3 300-6 600-fold7. The recent structure of ZIKV NS2B-NS3pro in complex with a boronate inhibitor has provided some important insights for drug design8. However, it remains still largely unknown the exact molecular mechanism of ZIKV NS3pro activation by NS2B, which requires a structure of the apo NS2B-NS3pro complex. An improved understanding of the mechanism of NS3pro activation can lead to identification of novel hot spots that can be targeted in rational drug design.
10.1038/cr.2016.116
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