The neutralization effect of montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies

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dc.contributor.authorDurdagi, Serdar
dc.contributor.authorAvsar, Timucin
dc.contributor.authorOrhan, Muge Didem
dc.contributor.authorSerhatli, Muge
dc.contributor.authorBalcioglu, Bertan Koray
dc.contributor.authorOzturk, Hasan Umit
dc.contributor.authorKayabolen, Alisan
dc.date.accessioned2024-02-23T14:16:30Z
dc.date.available2024-02-23T14:16:30Z
dc.date.issued2022
dc.departmentNEÜen_US
dc.description.abstractSmall molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the enzyme (main protease) inhibition-based assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T/hACE2+TMPRSS2, and virus neutralization assay using xCELLigence MP real-time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of montelukast both on the main protease enzyme inhibition and virus entry into the host cell (spike/ACE2). The virus neutralization assay results showed that SARS-CoV-2 virus activity was delayed with montelukast for 20 h on the infected cells. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and, if its effect is proved in clinical phase studies, it should be used against coronavirus disease 2019 (COVID-19).en_US
dc.description.sponsorshipScientific Research Projects Commission of Bahcesehir University [BAU.BAP.2020.01]; Scientific and Technological Research Council of Turkey (TUBITAK) [18AG003]en_US
dc.description.sponsorshipY This study was funded by Scientific Research Projects Commission of Bahcesehir University; project number: BAU.BAP.2020.01. This study was also funded by the Scientific and Technological Research Council of Turkey (TUB_ITAK), within the program number of 18AG003. We would like to thank Nestor Santiago-Gonzalvo (Cytiva) for his helpful discussion and support with the Biacoreexperiments.en_US
dc.identifier.doi10.1016/j.ymthe.2021.10.014
dc.identifier.endpage974en_US
dc.identifier.issn1525-0016
dc.identifier.issn1525-0024
dc.identifier.issue2en_US
dc.identifier.pmid34678509en_US
dc.identifier.scopus2-s2.0-85119042965en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage963en_US
dc.identifier.urihttps://doi.org/10.1016/j.ymthe.2021.10.014
dc.identifier.urihttps://hdl.handle.net/20.500.12452/12680
dc.identifier.volume30en_US
dc.identifier.wosWOS:000752448900006en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherCell Pressen_US
dc.relation.ispartofMolecular Therapyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[Keyword Not Available]en_US
dc.titleThe neutralization effect of montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studiesen_US
dc.typeArticleen_US

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