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

Abstract
Small 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).
AuthorsSerdar Durdagi, Timucin Avsar, Muge Didem Orhan, Muge Serhatli, Bertan Koray Balcioglu, Hasan Umit Ozturk, Alisan Kayabolen, Yuksel Cetin, Seyma Aydinlik, Tugba Bagci-Onder, Saban Tekin, Hasan Demirci, Mustafa Guzel, Atilla Akdemir, Seyma Calis, Lalehan Oktay, Ilayda Tolu, Yasar Enes Butun, Ece Erdemoglu, Alpsu Olkan, Nurettin Tokay, Şeyma Işık, Aysenur Ozcan, Elif Acar, Sehriban Buyukkilic, Yesim Yumak
JournalMolecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 30 Issue 2 Pg. 963-974 (02 02 2022) ISSN: 1525-0024 [Electronic] United States
PMID34678509 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Acetates
  • Cyclopropanes
  • Quinolines
  • Sulfides
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Serine Endopeptidases
  • TMPRSS2 protein, human
  • montelukast
Topics
  • A549 Cells
  • Acetates (chemistry, pharmacology)
  • Angiotensin-Converting Enzyme 2 (chemistry, metabolism)
  • Animals
  • Cell Survival (drug effects)
  • Chlorocebus aethiops
  • Cyclopropanes (chemistry, pharmacology)
  • Drug Repositioning
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Structure
  • Neutralization Tests
  • Protein Conformation
  • Quinolines (chemistry, pharmacology)
  • SARS-CoV-2 (drug effects, physiology)
  • Serine Endopeptidases (chemistry, metabolism)
  • Sulfides (chemistry, pharmacology)
  • Vero Cells
  • Virus Internalization (drug effects)

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