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Authors: Ghazizadeh et al.

Link to paper: https://www.biorxiv.org/content/10.1101/2020.05.12.091082v2

Journal/ Pre-Print: bioRxiv

Tags: Bioinformatics, Therapeutics, Drug discovery/ Drug repurposing

Research Highlights 

1. Used in vitro followed by high-throughput in silico screening strategy to screen drugs and identify candidates for reducing ACE2 expression in cardiac cells.

2. Identified a role for androgen signalling in SARS-CoV-2 infection.

3. Identified a link between elevated free androgen and COVID-19 complications in men.

Summary

Ghazizadeh et al. developed an in vitro system using hESC-derived cardiac cells to screen FDA-approved drugs for their efficacy in altering the expression of the SARS-CoV-2 receptor ACE2. They subsequently used their in vitro results to train an in silico model to screen over 9 million more drug-like compounds. By predicting drug-protein interactions they identified the androgen receptor signalling pathway as a target for drugs reducing ACE2 expression. Testing drugs that target the androgen receptor pathway, such as 5-alpha reductase inhibitors, they observed reduced levels of ACE2 and TMPRSS2. They further showed that activation of androgen receptor in cardiac cells increased viral receptor and co-receptor expression leading to increased Spike-RBD entry, whereas inhibition of the receptor had the opposite effect. Using UK Biobank data, the authors suggested that the free androgen index could be a potential indicator of COVID-19 severity in men.

Impact for SARS-CoV2/COVID19 research efforts

Androgen signalling as a modulator of ACE2 expression. Link between androgen imbalance and COVID-19 complications in men.

Study Type

· In vitro study.

· In silico analysis of public data sets.

Strengths and limitations of the paper

Novelty:

· Suggesting androgen receptor signalling as potential drug target. Novel deep learning strategy to screen drug-like compounds in silico

Standing in the field:

· It was known that being male is a major risk factor for complications after SARS-Cov2 infection. This study provides a potential explanation.

Appropriate statistics:

· Yes

Viral model used:

· None, artificial Spike protein RBD is used

Translatability:

· Yes, potential drug targets were predicted. No clinical investigation in this context.

Main limitations:

· Screening done in cell culture, only performed in cardiac cells, which were differentiated from human embryonic stem cells

· No in vivo tests in a virus model or efficacy tests yet (discussed drugs are FDA approved)

· Ketoconazole interactions are unclear from the figure (Fig. 3A)

· Cell to cell variability in ACE2 levels seems to be high following drug treatments.