Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/36533
Title: SYNTHESIS AND BIOLOGICAL EVALUATION OF SMALL MOLECULES AS INHIBITORS OF WEST NILE VIRUS NS2B-NS3 PROTEASE
Authors: SANJAY SAMANTA
Keywords: West Nile Virus, antiviral agents, bioorganic chemistry, docking studies, inhibitors, proteases.
Issue Date: 21-Aug-2012
Source: SANJAY SAMANTA (2012-08-21). SYNTHESIS AND BIOLOGICAL EVALUATION OF SMALL MOLECULES AS INHIBITORS OF WEST NILE VIRUS NS2B-NS3 PROTEASE. ScholarBank@NUS Repository.
Abstract: The mosquito borne West Nile Virus (WNV), a member of Flaviviridae family, is one of the major emerging pathogen to humans and animals. In recent years, clinical symptoms resulting from WNV have worsened in severity with an increased frequency in neuroinvasive diseases among the elderly. Despite the growing public health concern associated with WNV infection, till date there have been no successful antiviral therapies and vaccines for human use against WNV. The viral NS2B-NS3 protease has been identified as an attractive target for viral inhibition, due to its importance in viral replication and unique substrate preference. The objective of the research work reported in this thesis is to development potent inhibitors to the WNV NS2B-NS3 protease. A collection of compounds from our in-house compound library which have a history of antimicrobial, antiviral and anticancer activities was screened using the high-throughput screening (HTS) WNV protease assay. The hit compounds were further sorted out by cytotoxicity test and the non-toxic compounds were chosen for library synthesis and biological evaluation based on structural activity relationship (SAR) study. Optimization of initial hits led to the identification of novel, uncompetitive inhibitors. Further, chiral separation led to a highly potent uncompetitive inhibitor (-)-4-1a16 of WNV protease (IC50 = 2.2±0.7 µM) and in silico docking study suggested that the inhibitor (R)-4-1a16 interferes with the productive interactions of NS2B cofactor with the NS3 protease as an allosteric inhibitor. In addition, the R-enantiomer is the preferred isomer for the inhibition of the WNV NS2B-NS3 protease which is in agreement with our experimental inhibition result obtained for (-)-4-1a16.
URI: http://scholarbank.nus.edu.sg/handle/10635/36533
Appears in Collections:Ph.D Theses (Open)

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