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Two RNA tunnel inhibitors bind in highly conserved sites in Dengue virus NS5 polymerase: structural and functional studies.

Arora, Rishi and Liew, Chong Wai and Soh, Tingjin Sherryl and Otoo, Dorcas and Seh, Cheah Chen and Yue, Qing and Nilar, Shahul Hameed and Wang, Gang and Yokokawa, Fumiaki and Noble, Christian Guy and Chen, Yen-Liang and Shi, Pei-Yong and Lescar, Julien and Smith, Thomas and Benson, Timothy and Lim, Siew Pheng (2020) Two RNA tunnel inhibitors bind in highly conserved sites in Dengue virus NS5 polymerase: structural and functional studies. Journal of virology.

Abstract

Dengue virus (DENV) NS5 RNA-dependent RNA polymerase (RdRp), an important drug target, synthesizes viral RNA and is essential for viral replication. Whilst a number of allosteric inhibitors have been reported for Hepatitis C virus RdRp, few have been described for DENV RdRp. Following a diverse compound screening campaign and a rigorous hit-to-lead flow-chart combining biochemical and biophysical approaches, two DENV RdRp non-nucleoside inhibitors were identified and characterized. These inhibitors show low to high micro-molar inhibition in DENV RNA polymerization and cell-based assays. X-ray crystallography reveals that they bind in the enzyme RNA template tunnel. One compound (NITD-434) induced an allosteric pocket at the junction of the finger and palm subdomains by displacing residue V603 in motif B. Binding of another compound (NITD-640) ordered the finger loop preceding the F motif, close to the RNA template entrance. Most of the amino acid residues that interacted with these compounds are highly conserved in Flaviviruses. Both sites are important for polymerase de novo initiation and elongation activities and essential for viral replication. This work provides evidence that the RNA tunnel in DENV RdRp offers interesting target sites for inhibition.

Item Type: Article
Date Deposited: 20 Oct 2020 00:45
Last Modified: 20 Oct 2020 00:45
URI: https://oak.novartis.com/id/eprint/42825

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