Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp14/nsp10 Exoribonuclease

Overview

Journal Biochem J

Specialty Biochemistry

Date 2021 Jul 1

PMID 34198326

Citations 25

Authors

Berta Canal

Allison W McClure

Joseph F Curran

Mary Wu

Rachel Ulferts

Florian Weissmann

Jingkun Zeng

Agustina P Bertolin

Jennifer C Milligan

Souradeep Basu

Lucy S Drury

Tom D Deegan

Ryo Fujisawa

Emma L Roberts

Clovis Basier

Karim Labib

Rupert Beale

Michael Howell

John F X Diffley

Affiliations

Soon will be listed here.

Abstract

SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is an urgent need for effective antiviral treatments. The only currently approved antiviral treatment for COVID-19 is remdesivir, an inhibitor of viral genome replication. SARS-CoV-2 proliferation relies on the enzymatic activities of the non-structural proteins (nsp), which makes them interesting targets for the development of new antiviral treatments. With the aim to identify novel SARS-CoV-2 antivirals, we have purified the exoribonuclease/methyltransferase (nsp14) and its cofactor (nsp10) and developed biochemical assays compatible with high-throughput approaches to screen for exoribonuclease inhibitors. We have screened a library of over 5000 commercial compounds and identified patulin and aurintricarboxylic acid (ATA) as inhibitors of nsp14 exoribonuclease in vitro. We found that patulin and ATA inhibit replication of SARS-CoV-2 in a VERO E6 cell-culture model. These two new antiviral compounds will be valuable tools for further coronavirus research as well as potentially contributing to new therapeutic opportunities for COVID-19.

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