Discovery of potent non-nucleoside inhibitors of dengue viral RNA-dependent rna polymerase from fragment screening and structure-guided design

Siew Pheng Lim, Christian G. Noble, Shahul Nilar, Pei-Yong Shi, Fumiaki Yokokawa

Research output: Chapter in Book/Report/Conference proceedingChapter

2 Scopus citations

Abstract

Flavivirus NS5 RNA-dependent RNA polymerase (RdRp) is an important drug target. Whilst a number of allosteric inhibitors have been described for Hepatitis C virus RdRp, few have been described for DENV RdRp. In addition, compound screening campaigns have not yielded suitable leads for this enzyme. Using fragment-based screening via X-ray crystallography, we identified a biphenyl acetic acid fragment that binds to a novel pocket of the dengue virus (DENV) RdRp, in the thumb/palm interface, close to its active site (termed “N pocket”). Structure-guided optimization yielded nanomolar inhibitors of the RdRp de novo initiation activity, with low micromolar EC50 in DENV cell-based assays. Compound-resistant DENV replicons exhibited amino acid mutations that mapped to the N pocket. This is the first report of a class of pan-serotype and cell-active DENV RdRp inhibitors and provides a significant opportunity for rational design of novel therapeutics against this proven antiviral target.

Original languageEnglish (US)
Title of host publicationAdvances in Experimental Medicine and Biology
PublisherSpringer New York LLC
Pages187-198
Number of pages12
DOIs
StatePublished - Jan 1 2018

Publication series

NameAdvances in Experimental Medicine and Biology
Volume1062
ISSN (Print)0065-2598
ISSN (Electronic)2214-8019

Keywords

  • Anti-viral
  • Dengue virus
  • Drug discovery
  • Flaviviruses
  • Mechanism of inhibition
  • Rational design
  • Resistance phenotype
  • RNA dependent RNA polymerase
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Lim, S. P., Noble, C. G., Nilar, S., Shi, P-Y., & Yokokawa, F. (2018). Discovery of potent non-nucleoside inhibitors of dengue viral RNA-dependent rna polymerase from fragment screening and structure-guided design. In Advances in Experimental Medicine and Biology (pp. 187-198). (Advances in Experimental Medicine and Biology; Vol. 1062). Springer New York LLC. https://doi.org/10.1007/978-981-10-8727-1_14