Rajanish Giri

IIT, Mandi; IASc Associate: 2017

Rajanish Giri

Session 2C: Inaugural Lectures by Fellows/Associates

Investigating The Folding Of Zika Virus Proteins: Implications For Viral Pathogenesis And Inhibitor Discovery View Presentation

For almost sixty years, Zika virus (ZIKV) disease was considered as one of the neglected tropical diseases. The subsequent outbreaks after 2013 throughout the world had finally transformed the Zika disease as Public Health Emergency of International Concern (PhEIC) in Feb 2016 and further the spread got under control by late 2017. Acquiring a mosquito based and sexual mode of transmissions, the actual threat posed by ZIKV is associated with neurological defects like microcephaly and Guillain-Barre syndrome in new-borns as well as in adults respectively. The speaker will discuss his research on Zika virus proteins from structure–function and inhibitor discovery perspective. In general, the viruses have very limited number of proteins. In case of Zika virus, it encodes ten proteins: three structural and seven nonstructural proteins. Additionally, there are two small peptides as well, such as, Peptide 2K & Capsid Anchor. To begin with, we have raised a fundamental question that how these limited set of Zika proteins acquire multifunctional capabilities such that these can hijack the host system and induce the disease efficiently. Taking advantage from literature, we have found a strong correlation of intrinsically disordered proteins with multifunctional capabilities which was also shown to be highly implicated in viral proteomes. Therefore, based upon these studies, we have raised few questions to elucidate the molecular basis of Zika virus disease. What is the intrinsic disorder propensity in Zika virus? What are the biophysical properties of important enzymatic proteins of Zika virus in terms of folding and functioning? How does intrinsic flexibility of Zika virus proteins implicated in viral replication and propagation? In order to answer all these questions, we have firstly studied the role of intrinsic disorder in the maturation of proteins of Zika virus. Further, in NS2B-NS3 protease, we proved experimentally that the NS2B cofactor region of the viral protease is intrinsically disordered in nature. In fact, this is the case of disorder–function–paradigm. Another case is N-terminal Capsid region (1–30 residues), which folds upon binding to lipids and uses the disorder–function–paradigm for remodelling the host membranes. Additionally, we also performed the inhibitor discovery experiments and found that Hydroxychloroquine inhibits the Zika virus protease activity. Another finding of inhibitor discovery includes the Helicase enzyme inhibition by green tea molecule EGCG.