國家衛生研究院 NHRI:Item 3990099045/13378

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Title:	Synergistic inhibition of SARS-CoV-2 replication using disulfiram/ebselen and remdesivir
Authors:	Chen, T;Fei, CY;Chen, YP;Sargsyan, K;Chang, CP;Yuan, HS;Lim, C
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	The SARS-CoV-2 replication and transcription complex (RTC) comprising nonstructural protein (nsp) 2-16 plays crucial roles in viral replication, reducing the efficacy of broad-spectrum nucleoside analog drugs such as remdesivir and evading innate immune responses. Most studies target a specific viral component of the RTC such as the main protease or the RNA-dependent RNA polymerase. In contrast, our strategy is to target multiple conserved domains of the RTC to prevent SARS-CoV-2 genome replication and to create a high barrier to viral resistance and/or evasion of antiviral drugs. We show that the clinically safe Zn-ejector drugs disulfiram and ebselen can target conserved Zn(2+) sites in SARS-CoV-2 nsp13 and nsp14 and inhibit nsp13 ATPase and nsp14 exoribonuclease activities. As the SARS-CoV-2 nsp14 domain targeted by disulfiram/ebselen is involved in RNA fidelity control, our strategy allows coupling of the Zn-ejector drug with a broad-spectrum nucleoside analog that would otherwise be excised by the nsp14 proofreading domain. As proof-of-concept, we show that disulfiram/ebselen, when combined with remdesivir, can synergistically inhibit SARS-CoV-2 replication in Vero E6 cells. We present a mechanism of action and the advantages of our multitargeting strategy, which can be applied to any type of coronavirus with conserved Zn(2+) sites.
Date:	2021-04-09
Relation:	ACS Pharmacology and Translational Science. 2021 Apr 9;4(2):898-907.
Link to:	http://dx.doi.org/10.1021/acsptsci.1c00022
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85105035026
Appears in Collections:	[Chun-Ping Chang] Periodical Articles

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