Journal Article

Computational drug repurposing against SARS-CoV-2 reveals plasma membrane cholesterol depletion as key factor of antiviral drug activity

Szalai, Bence, Tóth, Dániel J., Várnai, Péter, Barsi, Szilvia, Papp, Henrietta, Valdeolivas, Alberto, Kuczmog, Anett, Madai, Mónika, Hunyady, László, Saez-Rodriguez, Julio, Jakab, Ferenc

2022

Overview

Comparing SARS-CoV-2 infection-induced gene expression signatures to drug treatment-induced gene expression signatures is a promising bioinformatic tool to repurpose existing drugs against SARS-CoV-2. The general hypothesis of signature-based drug repurposing is that drugs with inverse similarity to a disease signature can reverse disease phenotype and thus be effective against it. However, in the case of viral infection diseases, like SARS-CoV-2, infected cells also activate adaptive, antiviral pathways, so that the relationship between effective drug and disease signature can be more ambiguous. To address this question, we analysed gene expression data from in vitro SARS-CoV-2 infected cell lines, and gene expression signatures of drugs showing anti-SARS-CoV-2 activity. Our extensive functional genomic analysis showed that both infection and treatment with in vitro effective drugs leads to activation of antiviral pathways like NFkB and JAK-STAT. Based on the similarity—and not inverse similarity—between drug and infection-induced gene expression signatures, we were able to predict the in vitro antiviral activity of drugs. We also identified SREBF1/2, key regulators of lipid metabolising enzymes, as the most activated transcription factors by several in vitro effective antiviral drugs. Using a fluorescently labeled cholesterol sensor, we showed that these drugs decrease the cholesterol levels of plasma-membrane. Supplementing drug-treated cells with cholesterol reversed the in vitro antiviral effect, suggesting the depleting plasma-membrane cholesterol plays a key role in virus inhibitory mechanism. Our results can help to more effectively repurpose approved drugs against SARS-CoV-2, and also highlights key mechanisms behind their antiviral effect.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Antiviral activity / Antiviral agents / Antiviral Agents - pharmacology / Antiviral Agents - therapeutic use / Antiviral drugs / Biology and Life Sciences / Cell lines / Cell Membrane / Cell membranes / Cholesterol / Computer applications / Coronaviruses / COVID-19 / COVID-19 Drug Treatment / Depletion / Disease / Dosage and administration / Drug Repositioning - methods / Drugs / Enzymes / Funding / Gene expression / Genomic analysis / Health services / Humans / Infections / Linear programming / Lipids / Machine learning / Medical research / Medicine and health sciences / Membranes / Metabolism / NF-κB protein / Pathways / Phenotypes / Physiological aspects / Plasma / SARS-CoV-2 / Severe acute respiratory syndrome / Severe acute respiratory syndrome coronavirus 2 / Signatures / Similarity / Transcription factors / Viral diseases / Viral infections / Viruses