Natural Compounds Inhibit SARS-CoV-2 Nsp13 Unwinding and ATPase Enzyme Activities

Overview

Journal ACS Pharmacol Transl Sci

Publisher American Chemical Society

Specialty Biochemistry

Date 2022 Apr 18

PMID 35434533

Authors

Angela Corona

Krzysztof Wycisk

Carmine Talarico

Candida Manelfi

Jessica Milia

Rolando Cannalire

Francesca Esposito

Philip Gribbon

Andrea Zaliani

Daniela Iaconis

Andrea R Beccari

Vincenzo Summa

Marcin Nowotny

Enzo Tramontano

Affiliations

Soon will be listed here.

Abstract

SARS-CoV-2 infection is still spreading worldwide, and new antiviral therapies are an urgent need to complement the approved vaccine preparations. SARS-CoV-2 nps13 helicase is a validated drug target participating in the viral replication complex and possessing two associated activities: RNA unwinding and 5'-triphosphatase. In the search of SARS-CoV-2 direct antiviral agents, we established biochemical assays for both SARS-CoV-2 nps13-associated enzyme activities and screened both and a small in-house library of natural compounds. Myricetin, quercetin, kaempferol, and flavanone were found to inhibit the SARS-CoV-2 nps13 unwinding activity at nanomolar concentrations, while licoflavone C was shown to block both SARS-CoV-2 nps13 activities at micromolar concentrations. Mode of action studies showed that all compounds are nsp13 noncompetitive inhibitors versus ATP, while computational studies suggested that they can bind both nucleotide and 5'-RNA nsp13 binding sites, with licoflavone C showing a unique pattern of interaction with nsp13 amino acid residues. Overall, we report for the first time natural flavonoids as selective inhibitors of SARS-CoV-2 nps13 helicase with low micromolar activity.

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