Journal
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
Volume 4, Issue 2, Pages 898-907Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsptsci.1c00022
Keywords
COVID-19; structural Zn sites; nsp13; nsp14; replication and transcription complex
Categories
Funding
- Academia Sinica [AS-CFII-108-102]
- Ministry of Science and Technology, Taiwan [MOST 109-3114-Y-001-001]
- Ministry of Science & Technology, Taiwan [MOST-107-2113-M-001-018]
- Academia Sinica, Taiwan [AS-IA-107-L03, AS-IA-110-L02]
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This study targets multiple conserved domains of the SARS-CoV-2 replication and transcription complex (RTC) using clinically safe Zn-ejector drugs disulfiram and ebselen to inhibit key activities of nsp13 and nsp14, showing a synergistic inhibition of viral replication when combined with remdesivir.
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 Zn2+ 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 Zn2+ sites.
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