PT  - JOURNAL ARTICLE
AU  - Serdar Durdagi
AU  - Timucin Avsar
AU  - Muge Didem Orhan
AU  - Muge Serhatli
AU  - Bertan Koray Balcioglu
AU  - Hasan Umit Ozturk
AU  - Alisan Kayabolen
AU  - Yuksel Cetin
AU  - Seyma Aydinlik
AU  - Tugba Bagci-Onder
AU  - Saban Tekin
AU  - Hasan Demirci
AU  - Mustafa Guzel
AU  - Atilla Akdemir
AU  - Seyma Calis
AU  - Lalehan Oktay
AU  - Ilayda Tolu
AU  - Yasar Enes Butun
AU  - Ece Erdemoglu
AU  - Alpsu Olkan
AU  - Nurettin Tokay
AU  - Şeyma Işık
AU  - Aysenur Ozcan
AU  - Elif Acar
AU  - Sehriban Buyukkilic
AU  - Yesim Yumak
TI  - The neutralization effect of Montelukast on SARS-CoV-2 is shown by multiscale <em>in silico</em> simulations and combined <em>in vitro</em> studies
AID  - 10.1101/2020.12.26.424423
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.12.26.424423
4099  - http://biorxiv.org/content/early/2020/12/27/2020.12.26.424423.short
4100  - http://biorxiv.org/content/early/2020/12/27/2020.12.26.424423.full
AB  - 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 Fluorescent Resonance Energy Transfer (FRET)-based main protease enzyme inhibition assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T / hACE2, 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 virus entry into the host cell (Spike/ACE2) and on the main protease enzyme inhibition. The virus neutralization assay results showed that while no cytotoxicity of the Montelukast was observed at 12 μM concentration, the cell index time 50 (CIT50) value was delayed for 12 hours. Moreover, it was also shown that Favipiravir, a well-known antiviral used in COVID-19 therapy, should be used by 16-fold higher concentrations than Montelukast in order to have the same effect of Montelukast. 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.Competing Interest StatementThe authors have declared no competing interest.