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Montelukast is a dual-purpose inhibitor of SARS-CoV-2 infection and virus-induced IL-6 expression identified by structure-based drug repurposing. | LitMetric

Montelukast is a dual-purpose inhibitor of SARS-CoV-2 infection and virus-induced IL-6 expression identified by structure-based drug repurposing.

Comput Struct Biotechnol J

Institute of Molecular Immunology and Experimental Oncology, University Hospital München rechts der Isar, Technical University of Munich (TUM), Munich, Germany.

Published: January 2022

AI Article Synopsis

  • - Drug-repurposing has helped find treatments against SARS-CoV-2 by identifying a compound that can both inhibit the virus and reduce inflammation caused by immune cells during COVID-19.
  • - Researchers used structure-based modeling to screen a large library of drugs, ultimately identifying montelukast as a potential inhibitor that affects the structure of the virus's spike protein, thus preventing infection.
  • - Montelukast not only blocked SARS-CoV-2 infection in some variants but also reduced the release of IL-6, highlighting its dual function and suggesting that its mechanism of action may differ across various strains of the virus.

Article Abstract

Drug-repurposing has been instrumental to identify drugs preventing SARS-CoV-2 replication or attenuating the disease course of COVID-19. Here, we identify through structure-based drug-repurposing a dual-purpose inhibitor of SARS-CoV-2 infection and of IL-6 production by immune cells. We created a computational structure model of the receptor binding domain (RBD) of the SARS-CoV-2 spike 1 protein, and used this model for screening against a library of 6171 molecularly defined binding-sites from drug molecules. Molecular dynamics simulation of candidate molecules with high RBD binding-scores in docking analysis predicted montelukast, an antagonist of the cysteinyl-leukotriene-receptor, to disturb the RBD structure, and infection experiments demonstrated inhibition of SARS-CoV-2 infection, although montelukast binding was outside the ACE2-binding site. Molecular dynamics simulation of SARS-CoV-2 variant RBDs correctly predicted interference of montelukast with infection by the beta but not the more infectious alpha variant. With distinct binding sites for RBD and the leukotriene receptor, montelukast also prevented SARS-CoV-2-induced IL-6 release from immune cells. The inhibition of SARS-CoV-2 infection through a molecule binding distal to the ACE-binding site of the RBD points towards an allosteric mechanism that is not conserved in the more infectious alpha and delta SARS-CoV-2 variants.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8800171PMC
http://dx.doi.org/10.1016/j.csbj.2022.01.024DOI Listing

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