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

• Published in: Chemical Science 2020-09, Vol.11 (36), p.994-999
• Main Authors: Sargsyan, Karen, Lin, Chien-Chu, Chen, Ting, Grauffel, Cédric, Chen, Yi-Ping, Yang, Wei-Zen, Yuan, Hanna S, Lim, Carmay
• Format: Article
• Language: English
• Subjects: Chemistry; Coronaviruses; Domains; Drug resistance; Ejectors; Flow charts; Papain; Protease; Proteins; Replication; Severe acute respiratory syndrome coronavirus 2; Viral diseases; Viruses; Zinc compounds
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d0sc02646h

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. By combining evolutionary and physico-chemical principles, previously unknown druggable Zn-sites in multiple conserved SARS-CoV-2 domains have been identified.