Published January 1, 2022 | Version v1
Journal article Open

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

Creators

  • 1. Bahcesehir Univ, Sch Med, Dept Biophys, Computat Biol & Mol Simulat Lab, Istanbul, Turkey
  • 2. Bahcesehir Univ, Sch Med, Dept Med Biol, Istanbul, Turkey
  • 3. Sci & Technol Res Council Turkey TUBITAK, Genet Engn & Biotechnol Inst, Marmara Res Ctr MAM, TR-41470 Kocaeli, Turkey
  • 4. Koc Univ, Brain Canc Res & Therapy Lab, Sch Med, TR-34450 Istanbul, Turkey
  • 5. Koc Univ, Dept Mol Biol & Genet, TR-34450 Istanbul, Turkey
  • 6. Istanbul Medipol Univ, Int Sch Med, Dept Med Pharmacol, Istanbul, Turkey
  • 7. Bezmialem Vakif Univ, Fac Pharm, Dept Pharmacol, Comp Aided Drug Discovery Lab, Istanbul, Turkey

Description

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).

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