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Authors: Lo et al.

Link to paper: https://doi.org/10.1101/2020.05.26.116020

Journal/ Pre-Print: BioRxiv

Tags: Molecular Biology, Drug discovery/ Drug repurposing

Research Highlights 

1. Simeprevir inhibited SARS-CoV-2 replication (EC50 = 4.08µM) in Vero E6 cells, which is comparable to remdesivir.

2. Combination of remdesivir and simeprevir synergize to provide greater suppression of viral replication, without increasing cytotoxicity.

3. Simeprevir weakly inhibits MPro (IC50 = 13.7µM) and so is unlikely to account for suppression of SARS-CoV-2 replication on its own. Inhibition of PLPro activity or RdRP activity is not observed.

Summary

By screening a list of potential antiviral drugs against SARS-CoV-2 in Vero E6 cells, the study identified simeprevir as a potent candidate that suppresses SARS-CoV-2 replication at physiologically relevant concentration (10µm). Dose-response and cytotoxicity curves for each of simeprevir (EC50 = 4.08µM) and remdesivir (EC50 = 4.27µM) show that the two drugs have similar EC50 but simeprevir has a higher cytotoxicity. The authors also found synergism in viral replication inhibition activity between simeprevir (3.3µM) and remdesivir (1.1 to 10µM) without synergizing to increase cytotoxicity. Finally, in vitro enzyme activity assays showed that simeprevir weakly inhibits MPro (IC50 = 13.7µM) and does not inhibit PLPro or RdRP. The mechanism of viral inhibition by simeprevir is hence still unclear.

Impact for SARS-CoV2/COVID19 research efforts

Treat of SARS-CoV2/COVID19 positive individuals

Study Type

· In silico study

· In vitro study (assays and cell cultures)

Strengths and limitations of the paper

Novelty: Simeprevir shown to be a potent inhibitor of SARS-CoV-2 viral replication in vitro and synergizes with remdesivir without increasing cytotoxicity.

Standing in the field: Consistency for simeprevir inhibition of MPro measurement and CC50 in previous studies. Docking binding mode of simeprevir with MPro consistent with a recent docking study.

Appropriate statistics: Did not mention how statistics were carried out. Has error bars in the graphs but did not specify whether they are SD or SEM or anything else. Number of repeats of individual experiments is not mentioned.

Viral model used: SARS-CoV-2 virus (BetaCoV/Hong Kong/VM20001061/2020, SCoV2)

Translatability: A combination of simeprevir and remdesivir could be tested as a potential treatment for Covid-19. The synergy between the two drugs could allow for a lower dose of both drugs, thereby improving efficacy while reducing adverse effects.

Main limitations:

· All drugs are applied prior to viral infection, which does not represent when the drug will be administered i.e. after infection.

· Effect at different time points after SARS-CoV-2 infection in the presence of simeprevir is not studied. Only looked at 48hpi.

· The inhibitory effect of remdesivir at 10µM does not match in two different figures. (Fig1A&C and Fig2A)

· Inhibitory effect in Vero E6 cells may not mean inhibition in human lung cells. Further experiments with more relevant cell lines are needed.

· Confusion over cytotoxicity (Fig1) and cell viability (Fig2) and whether they are essentially the same is not mentioned.

· Primer extension assay not well descrived.