RT Journal Article
SR Electronic
T1 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
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.26.424423
DO 10.1101/2020.12.26.424423
A1 Durdagi, Serdar
A1 Avsar, Timucin
A1 Orhan, Muge Didem
A1 Serhatli, Muge
A1 Balcioglu, Bertan Koray
A1 Ozturk, Hasan Umit
A1 Kayabolen, Alisan
A1 Cetin, Yuksel
A1 Aydinlik, Seyma
A1 Bagci-Onder, Tugba
A1 Tekin, Saban
A1 Demirci, Hasan
A1 Guzel, Mustafa
A1 Akdemir, Atilla
A1 Calis, Seyma
A1 Oktay, Lalehan
A1 Tolu, Ilayda
A1 Butun, Yasar Enes
A1 Erdemoglu, Ece
A1 Olkan, Alpsu
A1 Tokay, Nurettin
A1 Işık, Şeyma
A1 Ozcan, Aysenur
A1 Acar, Elif
A1 Buyukkilic, Sehriban
A1 Yumak, Yesim
YR 2020
UL http://biorxiv.org/content/early/2020/12/27/2020.12.26.424423.abstract
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.