Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men
bioinformatics drug discovery/repurposing therapeutics
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
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.
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.
· In vitro study.
· In silico analysis of public data sets.
Strengths and limitations of the paper
· 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.
Viral model used:
· None, artificial Spike protein RBD is used
· Yes, potential drug targets were predicted. No clinical investigation in this context.
· 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.