دورية أكاديمية
The neutralization effect of montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies.
| العنوان: | 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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| المؤلفون: | Durdagi S; Department of Biophysics, Computational Biology and Molecular Simulations Laboratory, School of Medicine, Bahçeşehir University, Istanbul, Turkey. Electronic address: serdar.durdagi@med.bau.edu.tr., Avsar T; Department of Medical Biology, School of Medicine, Bahçeşehir University, Istanbul, Turkey., Orhan MD; Department of Medical Biology, School of Medicine, Bahçeşehir University, Istanbul, Turkey., Serhatli M; The Scientific and Technological Research Council of Turkey (TÜBİTAK) Marmara Research Center (MAM), Genetic Engineering and Biotechnology Institute, 41470 Gebze, Kocaeli., Balcioglu BK; The Scientific and Technological Research Council of Turkey (TÜBİTAK) Marmara Research Center (MAM), Genetic Engineering and Biotechnology Institute, 41470 Gebze, Kocaeli., Ozturk HU; The Scientific and Technological Research Council of Turkey (TÜBİTAK) Marmara Research Center (MAM), Genetic Engineering and Biotechnology Institute, 41470 Gebze, Kocaeli., Kayabolen A; Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, 34450 Istanbul, Turkey., Cetin Y; The Scientific and Technological Research Council of Turkey (TÜBİTAK) Marmara Research Center (MAM), Genetic Engineering and Biotechnology Institute, 41470 Gebze, Kocaeli., Aydinlik S; The Scientific and Technological Research Council of Turkey (TÜBİTAK) Marmara Research Center (MAM), Genetic Engineering and Biotechnology Institute, 41470 Gebze, Kocaeli., Bagci-Onder T; Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, 34450 Istanbul, Turkey; Koç University Research Center for Translational Medicine, 34450 Istanbul, Turkey., Tekin S; The Scientific and Technological Research Council of Turkey (TÜBİTAK) Marmara Research Center (MAM), Genetic Engineering and Biotechnology Institute, 41470 Gebze, Kocaeli; Department of Basic Sciences, Division of Medical Biology, Faculty of Medicine, University of Health Sciences, Istanbul, Turkey., Demirci H; Department of Molecular Biology and Genetics, Koç University, 34450 Istanbul, Turkey., Guzel M; Department of Medical Pharmacology, International School of Medicine, Istanbul Medipol University, Istanbul, Turkey., Akdemir A; Department of Pharmacology, Computer-aided Drug Discovery Laboratory, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul, Turkey., Calis S; Department of Medical Biology, School of Medicine, Bahçeşehir University, Istanbul, Turkey; Department of Molecular Biology-Genetics and Biotechnology, Istanbul Technical University, 34485 Istanbul, Turkey., Oktay L; Department of Biophysics, Computational Biology and Molecular Simulations Laboratory, School of Medicine, Bahçeşehir University, Istanbul, Turkey., Tolu I; Department of Biophysics, Computational Biology and Molecular Simulations Laboratory, School of Medicine, Bahçeşehir University, Istanbul, Turkey., Butun YE; Department of Medical Pharmacology, International School of Medicine, Istanbul Medipol University, Istanbul, Turkey., Erdemoglu E; Department of Biophysics, Computational Biology and Molecular Simulations Laboratory, School of Medicine, Bahçeşehir University, Istanbul, Turkey; Faculty of Medicine, Mersin University, Mersin, Turkey., Olkan A; Department of Biophysics, Computational Biology and Molecular Simulations Laboratory, School of Medicine, Bahçeşehir University, Istanbul, Turkey., Tokay N; The Scientific and Technological Research Council of Turkey (TÜBİTAK) Marmara Research Center (MAM), Genetic Engineering and Biotechnology Institute, 41470 Gebze, Kocaeli., Işık Ş; The Scientific and Technological Research Council of Turkey (TÜBİTAK) Marmara Research Center (MAM), Genetic Engineering and Biotechnology Institute, 41470 Gebze, Kocaeli., Ozcan A; Department of Biophysics, Computational Biology and Molecular Simulations Laboratory, School of Medicine, Bahçeşehir University, Istanbul, Turkey; Faculty of Medicine, Istanbul Medeniyet University, Istanbul, Turkey., Acar E; Department of Biophysics, Computational Biology and Molecular Simulations Laboratory, School of Medicine, Bahçeşehir University, Istanbul, Turkey; Faculty of Medicine, Istanbul Medeniyet University, Istanbul, Turkey., Buyukkilic S; Department of Biophysics, Computational Biology and Molecular Simulations Laboratory, School of Medicine, Bahçeşehir University, Istanbul, Turkey; Faculty of Science, Necmettin Erbakan University, Konya, Turkey., Yumak Y; Department of Biophysics, Computational Biology and Molecular Simulations Laboratory, School of Medicine, Bahçeşehir University, Istanbul, Turkey; Faculty of Science and Letters, Tokat Gaziosmanpaşa University, Tokat, Turkey. |
| المصدر: | Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2022 Feb 02; Vol. 30 (2), pp. 963-974. Date of Electronic Publication: 2021 Oct 19. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 100890581 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1525-0024 (Electronic) Linking ISSN: 15250016 NLM ISO Abbreviation: Mol Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2017- : Cambridge, MA : Cell Press Original Publication: San Diego, CA : Academic Press, 2000- |
| مواضيع طبية MeSH: | Acetates/*pharmacology , Angiotensin-Converting Enzyme 2/*metabolism , Cyclopropanes/*pharmacology , Quinolines/*pharmacology , SARS-CoV-2/*physiology , Serine Endopeptidases/*metabolism , Sulfides/*pharmacology, A549 Cells ; Acetates/chemistry ; Angiotensin-Converting Enzyme 2/chemistry ; Animals ; Cell Survival/drug effects ; Chlorocebus aethiops ; Cyclopropanes/chemistry ; Drug Repositioning ; HEK293 Cells ; Humans ; Models, Molecular ; Molecular Docking Simulation ; Molecular Structure ; Neutralization Tests ; Protein Conformation ; Quinolines/chemistry ; SARS-CoV-2/drug effects ; Serine Endopeptidases/chemistry ; Sulfides/chemistry ; Vero Cells ; Virus Internalization/drug effects |
| مستخلص: | 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). Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.) |
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| فهرسة مساهمة: | Keywords: COVID-19; MD simulations; drug repurposing; molecular docking; montelukast; pseudovirus neutralization; virus neutralization |
| المشرفين على المادة: | 0 (Acetates) 0 (Cyclopropanes) 0 (Quinolines) 0 (Sulfides) EC 3.4.17.23 (ACE2 protein, human) EC 3.4.17.23 (Angiotensin-Converting Enzyme 2) EC 3.4.21.- (Serine Endopeptidases) EC 3.4.21.- (TMPRSS2 protein, human) MHM278SD3E (montelukast) |
| تواريخ الأحداث: | Date Created: 20211022 Date Completed: 20220210 Latest Revision: 20220218 |
| رمز التحديث: | 20240829 |
| مُعرف محوري في PubMed: | PMC8524809 |
| DOI: | 10.1016/j.ymthe.2021.10.014 |
| PMID: | 34678509 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1525-0024 |
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| DOI: | 10.1016/j.ymthe.2021.10.014 |