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Luedemann, M.* ; Stadler, D.* ; Cheng, C.C.* ; Protzer, U. ; Knolle, P.A.* ; Donakonda, S.*

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

Comp. Struc. Biotech. J. 20, 799-811 (2022)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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 in silico 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Structural Modeling ; Binding Site Similarity ; Docking ; Molecular Dynamics Simulations ; Neutralization ; Sars-cov-2
ISSN (print) / ISBN 2001-0370
e-ISSN 2001-0370
Zeitschrift Computational and Structural Biotechnology Journal
Quellenangaben Band: 20 , Heft: , Seiten: 799-811 Artikelnummer: , Supplement: ,
Verlag Research Network of Computational and Structural Biotechnology (RNCSB)
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
Förderungen Helmholtz Association
Deutsches Zentrum für Infektionsforschung
MDC
Michael Sattler Helmholtz Zentrum Munich