Multi-targeting of functional cysteines in multiple conserved SARS-CoV-2 domains by clinically safe Zn-ejectors.

Chemical Science
Karen SargsyanCarmay Lim

Abstract

We present a near-term treatment strategy to tackle pandemic outbreaks of coronaviruses with no specific drugs/vaccines by combining evolutionary and physical principles to identify conserved viral domains containing druggable Zn-sites that can be targeted by clinically safe Zn-ejecting compounds. By applying this strategy to SARS-CoV-2 polyprotein-1ab, we predicted multiple labile Zn-sites in papain-like cysteine protease (PLpro), nsp10 transcription factor, and nsp13 helicase. These are attractive drug targets because they are highly conserved among coronaviruses and play vital structural/catalytic roles in viral proteins indispensable for virus replication. We show that five Zn-ejectors can release Zn2+ from PLpro and nsp10, and clinically-safe disulfiram and ebselen can not only covalently bind to the Zn-bound cysteines in both proteins, but also inhibit PLpro protease. We propose combining disulfiram/ebselen with broad-spectrum antivirals/drugs to target different conserved domains acting at various stages of the virus life cycle to synergistically inhibit SARS-CoV-2 replication and reduce the emergence of drug resistance.

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Citations

Apr 16, 2021·ACS Pharmacology & Translational Science·Ting ChenCarmay Lim
May 22, 2021·Molecular Informatics·Pablo Andrei NogaraJoão Batista Teixeira Rocha
May 1, 2021·International Journal of Molecular Sciences·Adam StasiulewiczJoanna I Sulkowska
Oct 9, 2020·Dalton Transactions : an International Journal of Inorganic Chemistry·Raphael E F de PaivaFernando R G Bergamini
May 19, 2021·Chembiochem : a European Journal of Chemical Biology·Johannes Karges, Seth M Cohen
Jun 25, 2021·Chemical Science·Yangyang ChengStefan Matile
Sep 2, 2021·JACS Au·Quentin LaurentStefan Matile
Oct 26, 2021·Dalton Transactions : an International Journal of Inorganic Chemistry·Danielle van der WesthuizenOrde Q Munro

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Datasets Mentioned

BETA
MN908947.3

Methods Mentioned

BETA
protein folding

Software Mentioned

BLASTp
SCRWL4
MODELLER

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