Multi-Targeting of Functional Cysteines in Multiple Conserved SARS-CoV-2 Domains by Clinically Safe Zn-ejectors

24 April 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

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 viral replication. We show that five Zn-ejectors can release Zn2+ from PLpro and nsp10, and clinically-safe disulfiram and ebselen can covalently bind to the Zn-bound/catalytic cysteines in both proteins. Notably, disulfiram and ebselen inhibited PLpro protease activity with IC50 in the μM range. 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.

Keywords

coronavirus
COVID-19
structural Zn
cysteine reactivity
papain-like protease
nsp10
nsp13
disulfiram
ebselen

Supplementary materials

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Title
Zn-ejectors SARS-CoV-2 SI
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