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

Autor: Ece Erdemoglu, Nurettin Tokay, Şaban Tekin, Lalehan Oktay, Elif Acar, Hasan DeMirci, Timucin Avsar, Alpsu Olkan, Yesim Yumak, Bertan Koray Balcioglu, Muge Didem Orhan, Seyma Calis, Hasan Umit Ozturk, Sehriban Buyukkilic, Yuksel Cetin, Yasar Enes Butun, Aysenur Ozcan, Atilla Akdemir, Muge Serhatli, Şeyma Işık, Tugba Bagci-Onder, Seyma Aydinlik, Mustafa Guzel, Serdar Durdagi, Alisan Kayabolen, Ilayda Tolu
Přispěvatelé: Kayabölen, Alişan, Önder, Tuğba Bağcı (ORCID 0000-0003-3646-2613 & YÖK ID 184359), Demirci, Hasan (ORCID 0000-0002-9135-5397 & YÖK ID 307350), Durdağı, Serdar, Avşar, Timuçin, Orhan, Müge Didem, Serhatlı, Müge, Balcıoğlu, Bertan Koray, Öztürk, Hasan Ümit, Çetin, Yüksel, Aydınlık, Şeyma, Tekin, Şaban, Güzel, Mustafa, Akdemir, Atilla, Çalış, Şeyma, Oktay, Lalehan, Tolu, İlayda, Bütün, Yaşar Enes, Erdemoğlu, Ece, Olkan, Alpsu, Tokay, Nurettin, Işık, Şeyma, Özcan, Ayşenur, Acar, Elif, Büyükkılıç, Şehriban, Yumak, Yeşim, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, College of Sciences, Department of Molecular Biology and Genetics, AKDEMİR, ATİLLA
Rok vydání: 2021
Předmět:
Cyclopropanes
Models
Molecular
Vitro Studies
pseudovirus neutralization
Protein Conformation
medicine.medical_treatment
Pharmacology
Acetates
Neutralization
Drug Discovery
Chlorocebus aethiops
MD simulations
Leukotriene
drug repurposing
Molecular Structure
Chemistry
Biotechnology and applied microbiology
Serine Endopeptidases
Small molecule
Molecular Docking Simulation
montelukast
virus neutralization
Quinolines
Molecular Medicine
Original Article
Angiotensin-Converting Enzyme 2
medicine.drug
Cell Survival
COVID-19
Drug repurposing
Molecular docking
Montelukast
Pseudovirus Neutralization
Virus neutralization
Sulfides
Virus
Viral entry
Neutralization Tests
Genetics
medicine
Animals
Humans
Molecular Biology
Vero Cells
Protease
SARS-CoV-2
Silico Simulations
Drug Repositioning
molecular docking
Virus Internalization
In vitro
respiratory tract diseases
HEK293 Cells
A549 Cells
Zdroj: Molecular Therapy
ISSN: 1525-0024
Popis: Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of 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 the 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 hours 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 proven in clinical phase studies, it should be used against COVID-19.
Graphical abstract
In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist Montelukast that simultaneously targets two important drug targets of SARS-CoV-2. Montelukast shows its effect both on the main protease and Spike/ACE2. The virus neutralization assay results showed that SARS-CoV-2 activity was delayed with Montelukast for 20 hours on the infected cells.
Databáze: OpenAIRE
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