Identification of a Broad-Spectrum Viral Inhibitor Targeting a Novel Allosteric Site in the RNA-Dependent RNA Polymerases of Dengue Virus and Norovirus

Frontiers in Microbiology
Dongrong YiShan Cen

Abstract

All RNA viruses encode the RNA-dependent RNA polymerase (RdRp) which replicates and transcribes viral RNA. This essential viral enzyme does not exist in mammalian cells, thus presents a main target for the development of antiviral drugs with potential pan-antiviral activity. In this study, we take advantage of the structurally equivalent site in the dengue virus (DENV) RdRp, the N-pocket, and in the human norovirus (hNV) RdRp, the B-site, and performed a parallel structure-based virtual screening to discover compounds that can inhibit the RdRps of both hNV and DENV. We successfully identified a small molecule called Entrectinib (RAI-13) as a potent inhibitor of both hNV and DENV infection. Specifically, RAI-13 binds directly to hNV and DENV RdRps, effectively inhibits the polymerase activity in the in vitro biochemical assays, and exhibits does-responsive inhibition of murine norovirus (MNV) and DENV2 infection with IC50 values of 2.01 and 2.43 μM, respectively. Most promisingly, RAI-13 inhibits hepatitis C virus (HCV) infection by 95% at the 2 μM concentration. We have therefore discovered a small molecule compound that targets an allosteric site that is shared by different viral RdRps and strongly inhibits multiple pathogenic...Continue Reading

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Citations

Dec 9, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Francesca PicarazziMattia Mori
Feb 23, 2021·Acta Pharmaceutica Sinica. B·Quanjie LiShan Cen
Jul 19, 2021·European Journal of Medicinal Chemistry·Igor José Dos Santos NascimentoEdeildo Ferreira da Silva-Júnior
Jul 28, 2021·Molecular Aspects of Medicine·Sonam BhatiaDeepak T Nair

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Datasets Mentioned

BETA
KT239579.2
AY662691.1

Methods Mentioned

BETA
transfection
Protein assay
biosensors
biosensor
size exclusion chromatography
Assay

Software Mentioned

TargetMol
AutoDock Vina
Auto Dock Vina
Data Analysis
MMFF94
kClust
AutoDockTools ADT
Amber11
GraphPad
Open Babel toolkit

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