Multi-targeting of functional cysteines in multiple conserved SARS-CoV-2 domains by clinically safe Zn-ejectors. Issue 36 (4th September 2020)

• Record Type: Journal Article
• Authors: Sargsyan, Karen; Lin, Chien-Chu; Chen, Ting; Grauffel, Cédric; Chen, Yi-Ping; Yang, Wei-Zen; Yuan, Hanna S.; Lim, Carmay
• Is Part Of: Chemical science. Volume 11:Issue 36(2020)
• Page Start: 9904
• Page End: 9909
• Publication Date: 2020-09-04
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d0sc02646h
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : By combining evolutionary and physico-chemical principles, previously unknown druggable Zn-sites in multiple conserved SARS-CoV-2 domains have been identified. 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 (PL pro ), 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 Zn 2+ from PL pro and nsp10, and clinically-safe disulfiram and ebselen can not only covalently bind to the Zn-bound cysteines in both proteins, but also inhibit PL pro 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.