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林小喬博士

特聘研究員
  • +886-2-2789-9043 (Lab) (Room No: N117)
  • +886-2-2652-3031 (Office)
  • +886-2-2788-7641 (Fax)

Specialty:
  • Computational Biophysics
  • Computational Chemistry
  • Bioinformatics

Education and Positions:
  • 1984, Ph.D. in Chemical Physics, University of Minnesota, Minneapolis

    1979, B.S. in Chemistry, Royal Holloway College, London University

     


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

Dr. Lim, Carmay
ACS Pharmacology & Translational Science, Mar 26, 2021

 

 

 

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 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.