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

1 Citation (Scopus)

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

Fingerprint

RNA Replicase
Dengue
Viral RNA
DNA-Directed RNA Polymerases
Dengue Virus
Viruses
Screening
Flavivirus
Replicon
X ray crystallography
X Ray Crystallography
Thumb
Acetic Acid
Hepacivirus
Antiviral Agents
Assays
Catalytic Domain
Amino Acids
Mutation
Enzymes

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)

Cite this

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

Discovery of potent non-nucleoside inhibitors of dengue viral RNA-dependent rna polymerase from fragment screening and structure-guided design. / Lim, Siew Pheng; Noble, Christian G.; Nilar, Shahul; Shi, Pei-Yong; Yokokawa, Fumiaki.

Advances in Experimental Medicine and Biology. Springer New York LLC, 2018. p. 187-198 (Advances in Experimental Medicine and Biology; Vol. 1062).

Research output: Chapter in Book/Report/Conference proceedingChapter

Lim, SP, Noble, CG, 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. Advances in Experimental Medicine and Biology, vol. 1062, Springer New York LLC, pp. 187-198. https://doi.org/10.1007/978-981-10-8727-1_14
Lim SP, Noble CG, Nilar S, Shi P-Y, Yokokawa F. 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. Springer New York LLC. 2018. p. 187-198. (Advances in Experimental Medicine and Biology). https://doi.org/10.1007/978-981-10-8727-1_14
Lim, Siew Pheng ; Noble, Christian G. ; Nilar, Shahul ; Shi, Pei-Yong ; Yokokawa, Fumiaki. / Discovery of potent non-nucleoside inhibitors of dengue viral RNA-dependent rna polymerase from fragment screening and structure-guided design. Advances in Experimental Medicine and Biology. Springer New York LLC, 2018. pp. 187-198 (Advances in Experimental Medicine and Biology).
@inbook{fc5c4a0330da47539c194717049041a0,
title = "Discovery of potent non-nucleoside inhibitors of dengue viral RNA-dependent rna polymerase from fragment screening and structure-guided design",
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.",
keywords = "Anti-viral, Dengue virus, Drug discovery, Flaviviruses, Mechanism of inhibition, Rational design, Resistance phenotype, RNA dependent RNA polymerase, X-ray crystallography",
author = "Lim, {Siew Pheng} and Noble, {Christian G.} and Shahul Nilar and Pei-Yong Shi and Fumiaki Yokokawa",
year = "2018",
month = "1",
day = "1",
doi = "10.1007/978-981-10-8727-1_14",
language = "English (US)",
series = "Advances in Experimental Medicine and Biology",
publisher = "Springer New York LLC",
pages = "187--198",
booktitle = "Advances in Experimental Medicine and Biology",

}

TY - CHAP

T1 - Discovery of potent non-nucleoside inhibitors of dengue viral RNA-dependent rna polymerase from fragment screening and structure-guided design

AU - Lim, Siew Pheng

AU - Noble, Christian G.

AU - Nilar, Shahul

AU - Shi, Pei-Yong

AU - Yokokawa, Fumiaki

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Anti-viral

KW - Dengue virus

KW - Drug discovery

KW - Flaviviruses

KW - Mechanism of inhibition

KW - Rational design

KW - Resistance phenotype

KW - RNA dependent RNA polymerase

KW - X-ray crystallography

UR - http://www.scopus.com/inward/record.url?scp=85047963892&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047963892&partnerID=8YFLogxK

U2 - 10.1007/978-981-10-8727-1_14

DO - 10.1007/978-981-10-8727-1_14

M3 - Chapter

C2 - 29845534

AN - SCOPUS:85047963892

T3 - Advances in Experimental Medicine and Biology

SP - 187

EP - 198

BT - Advances in Experimental Medicine and Biology

PB - Springer New York LLC

ER -