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

Chen et al., ACS Pharmacology & Translational Science, doi:10.1021/acsptsci.1c00022

Mar 2021

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In Vitro study showing that disulfiram and ebselen, when combined with remdesivir, synergistically inhibit SARS-CoV-2 replication in Vero E6 cells. Authors demonstrate that these clinically safe Zn-ejector drugs target conserved Zn²⁺ sites in SARS-CoV-2 nonstructural proteins (nsp) 13 and 14, inhibiting nsp13 ATPase and nsp14 exoribonuclease activities, which disrupts viral RNA replication and fidelity control. This multitarget approach enhances remdesivir’s efficacy by preventing its excision by nsp14’s proofreading domain, creating a high barrier to viral resistance. Synergy was quantified using high-content imaging and SynergyFinder, with low-dose combinations reducing infection rates significantly compared to no treatment.

Gérard, Zhou, Wu, Kamo, Choi, Kim show increased risk of acute kidney injury with remdesivir. Leo, Briciu, Muntean, Petrov show increased risk of liver injury with remdesivir.

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Chen et al., 26 Mar 2021, Taiwan, peer-reviewed, 7 authors. Contact: carmay@gate.sinica.edu.tw, hanna@sinica.edu.tw.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Remdesivir All

Abstract: Supporting Information Synergistic Inhibition of SARS-CoV-2 Replication using Disulfiram/Ebselen and Remdesivir Ting Chen1, Cheng-Yin Fei2, Yi-Ping Chen2, Karen Sargsyan1, ChunPing Chang3, Hanna S. Yuan2*, and Carmay Lim1,4* 1Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan 2Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan 3Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 350, Taiwan 4Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan Corresponding author’s e-mail: carmay@gate.sinica.edu.tw or hanna@sinica.edu.tw S-1 Supplementary Figure S1. Synergistic antiviral potential of disulfiram and remdesivir. (A) A low-dosing window of synergistic antiviral effect in Vero E6 cells treated with remdesivir and disulfiram was determined. The fluorescent signal was quantified by high-content imaging analysis system (Molecular Devices) and the infection rate of no compound treatment was set as 100%. To detect SARS-CoV-2, the cells were stained with anti-SARS-CoV-2 N protein antibody and anti-human IgG-488 (shown in green). (B) The corresponding dose-based synergy scores of remdesivir and disulfiram was plotted by SynergyFinder. S-2 Supplementary Figure S2. Synergistic antiviral potential of ebselen and remdesivir. (A) A low-dosing window of synergistic antiviral effect in Vero E6 cells treated with remdesivir and ebselen was determined. The fluorescent signal was quantified by high-content imaging analysis system (Molecular Devices) and the infection rate of no compound treatment was set as 100%. To detect SARS-CoV-2, the cells were stained with anti-SARS-CoV-2 N protein antibody and anti-human IgG-488 (shown in green). (B) The corresponding dose-based synergy scores of remdesivir and ebselen was plotted by SynergyFinder. S-3

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