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Synergistic Inhibition of SARS-CoV-2 Replication Using Disulfiram/Ebselen and Remdesivir

[Image: see text] 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 targ...

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Detalles Bibliográficos
Autores principales: Chen, Ting, Fei, Cheng-Yin, Chen, Yi-Ping, Sargsyan, Karen, Chang, Chun-Ping, Yuan, Hanna S., Lim, Carmay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009100/
https://www.ncbi.nlm.nih.gov/pubmed/33855277
http://dx.doi.org/10.1021/acsptsci.1c00022
Descripción
Sumario:[Image: see text] 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.