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Authors: Pruijssers et al.

Link to paper: https://doi.org/10.1101/2020.04.27.064279

Journal/ Pre-Print: BioRxiv

Tags: Drug discovery/Drug repurposing, Molecular biology, Modelling, Virology, Therapeutics

Research Highlights 

1. Remdesivir decreases viral load and improves pulmonary function in mice infected with chimeric SARS-CoV-1 with SARS-CoV-2 RdRp.

2. Remdesivir potently inhibits SARS-COV-2 replication in cell lines with high capacity to metabolise and activate Remdesivir.

3. Structural modelling suggests that Remdesivir can be used as a broad-spectrum CoV drug.

Summary

Using in silico structure modelling and sequence alignment, the study predicts efficient incorporation of Remdesivir metabolite (RDV-TP) into SARS-CoV-2 polymerase and demonstrates high structural conservation of the active site across human CoV polymerases. The study provides more evidence that Remdesivir inhibits SARS-CoV-2 replication in different cell lines and suggests a potential link between the Remdesivir metabolite level and the antiviral potency of Remdesivir in a cell line. Most importantly, through infecting mice with recombinant SARS-CoV-1 viruses with SARS-CoV-2 polymerase, the study demonstrates that Remdesivir can effectively lower viral titre and improve pulmonary function in vivo.

Impact for SARS-CoV2/COVID19 research efforts

Treat of SARS-CoV2/COVID19 positive individuals

Study Type

· In silico study / bioinformatics study

· In vitro study

· In vivo study (mouse)

Strengths and limitations of the paper

Novelty:

First study showing that Remdesivir can potently inhibit viruses containing SARS-CoV-2 polymerase in vivo in a mouse model.

Standing in the field:

Cell culture experiments agree with previous literature, suggesting that Remdesivir has high viral inhibition potency in some cell lines (Calu3 and HAEs) but a low potent inhibition of SARS-CoV-2 in cell lines with low metabolic capacity for Remdesivir (e.g. Vero E6).

Modelling data could not explain well the mechanism of Remdesivir resistance caused by a point mutation (F480) and contradicts the modelling result in a different publication (Shannon et al., 2020). Furthermore, the structure basis of Remdesivir inhibition of the SARS-CoV2 RdRp has been recently published (Yin et al., 2020, Science).

Mouse model shows similar promising result to studies using other animal models, e.g. rhesus macaques.

Very recent clinical trials administering Remdesivir to human COVID19 patients have produced conflicting results on the efficacy of the drug (Wang et al., 2020, The Lancet; discussed by Ledford, 2020, Nature).

Appropriate statistics:

The number of biological replicates varies between individual experiments, some have less than three replicates (e.g. Figure 2, 4).

SEM, or SD, are used to represent variation in some figures where SD, or SEM, is more appropriate (e.g. Figure 2, 4)

Viral model used:

In vitro studies: SARS-CoV-2 (2019-nCoV/USA-WA1/2020)

In vivo study: chimeric mouse-adapted SARS-CoV1 MA15 variant encoding the SARS-CoV2 RdRp (‘SARS1/SARS2-RdRp’) (with and without nanoluciferase reporter)

Translatability:

Provides further in vitro and tentative in vivo evidence in mice that Remdesivir should be subjected to clinical trials as a promising therapeutic drug against SARS-CoV-2.

Remdesivir has been recently approved by the FDA for emergency use in humans with severe COVID19.

Main limitations:

- Supplementary figures and tables not available so unable to assess data.

- Very low graphic quality of the structure model in Fig 1.

- Although they could not measure the direct effect of Remdesivir on SARS-CoV-2 polymerase in mice, they did not discuss the possibility that in vivo inhibition could be due to other physiological effect.

- The in vivo experiments should be performed with SARS-CoV2 not the chimeric virus SARS-CoV1 differs from SARS-CoV2 in more than just the RdRp.

- Have suggested Remdesivir as a broad-spectrum drug based on modelling, without comparing its efficacy in different coronaviruses (HCoV-OC43, -229E, SARS-CoV-1, HKU1) in cell culture.

- They don’t include a comparison of SARS1/SARS2-RdRp and the actual SARS-CoV2 isolate in cells therefore how does this chimeric virus which was used for the in vivo experiments compare to SARS-CoV2?

- No histology of lungs included to show accompany the lung haemorrhage score, which in the text is described as significantly reduced but has a p-value of 0.069.

- Would be useful to know the effect on viral titre at an earlier timepoint in addition to the 5 d.p.i. shown here: there is no information on the kinetics of the effects of Remdesivir as a therapeutic in vivo.

- Here Remdesivir was administered 1 d.p.i. in vivo, would this work when administered at a later time point, as would be more clinically relevant to treatment of humans? And is it only effective when given i.v. as in this study?

- No discussion of potential side effects when Remdesivir was administered in vivo.

- 10 of the authors are employees of the company which produces Remdesivir and GM-441524