Enisamium is a small molecule inhibitor of the influenza A virus and SARS-CoV-2 RNA polymerases

Authors: Walker et al.,

Link to paper: https://doi.org/10.1101/2020.04.21.053017

Journal/ Pre-Print: BioRxiv

Tags: Drug discovery/Drug repurposing, Antiviral therapeutics, RNA viruses

Research Highlights 

1. Suggests that enisamium, an approved drug against influenza, is a potential therapeutic option against SARS-CoV-2 infection.

2. Identifies a putative hydroxylated metabolite of enisamium, VR17-04, which has a higher in vitro inhibitory activity against both influenza and SARS-CoV-2 RNA polymerase complexes

Summary

Using in vitro assays, the study confirms that enisamium, a clinically approved drug against influenza virus, possesses antiviral activity and inhibits the function of influenza polymerase. In vitro assays also show that enisamium can inhibit the activity of SARS-CoV-2 RNA polymerase complex, which could potentially lead to inhibition of viral growth. The study further demonstrates that a putative hydroxylated metabolite of enisamium, VR17-04, has a more potent inhibitory effect than enisamium in both influenza and SARS-CoV-2 RNA synthesis. The authors hence suggest the therapeutic importance of enisamium and its putative derivatives.

Impact for SARS-CoV2/COVID19 research efforts

Understand the virology and/or cell biology of SARS-CoV2/COVID19

Treat of SARS-CoV2/COVID19 positive individuals

Study Type

· In vitro study (cell culture and biochemical assays with purified proteins)

Strengths and limitations of the paper

Novelty: Shown for the first time that enisamium and its putative metabolite can inhibit RNA synthesis in SARS-CoV-2.

Standing in the field: The growth and RNA synthesis inhibitory effect of enisamium on influenza virus is in agreement with previous literature.

Appropriate statistics: No statistics are used. All quantification data are from n = 3 independent experiments.

Viral model used: No viruses were used. Recombinant proteins were generated from

- A/WSN/33 (H1N1) influenza virus

- SARS-CoV-2 (strain not given)

Translatability:

Early stage of translation. Enisamium is already a licensed drug and has been previously identified by the WHO as a candidate therapeutic against SARS-CoV2. However, it is essential to show that enisamium has antiviral activity against fully infectious SARS-CoV2 in vivo before it’s suitability as a treatment for SARS-CoV2 in the clinic is determined.

Main limitations:

- No cell culture data on SARS-CoV-2 viral inhibition. The data showing the inhibition of SARS-CoV2 RNA polymerase by enisamium are based on purified proteins from the virus used in an in vitro assay.

- There is no discussion about potential reasons why the putative metabolite, VR17-04, has a stronger inhibitory potency than enisamium and if it would be able to be used as a therapeutic.

- There is no discussion about the concentrations of the inhibitor used throughout this study, and whether these concentrations are physiologically relevant (e.g. toxicity etc.)

- The primer extension data would have benefitted from using a different concentration range.