The neutralization effect of Montelukast on SARS-CoV-2 is shown by multiscalein silicosimulations and combinedin vitrostudies

Abstract

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.

The Petasites hybridus CO2-extract (Ze 339) blocks SARS-CoV-2 replication in vitro

“…In our current study, a pre-incubation of cells with the test compounds for 2 h prior to virus infection had a clear positive effect, suggesting a possible prophylactic role also for the petasins. While the montelukast IC 50 values were at 18.82 µM and 25 µM in in vitro cell culture models of SARS-CoV-2 activity [73,74], the IC 50 s for Ze 339, isopetasin and neopetasin determined in the current study were significantly lower. The visibly shallower inhibition curves of the petasin compounds compared to the antiviral mechanism of remdesivir could suggest a more complex mode of interference with the viral life cycle which is supported by the above mentioned various mechanisms of action of Ze 339.…”

“…It is further worth mentioning that the mechanism of anti-inflammatory action of Ze 339 is comparable to that of montelukast and zileuton, which are currently under discussion as therapeutic candidates for the treatment of COVID-19 [25][26][27][28][29]. In a recent study by Durdagi et al [73] demonstrated the neutralization effect of montelukast on SARS-CoV-2 in vitro by showing that virus replication could be significantly delayed. The authors suggested to consider montelukast for prophylactic treatment.…”

The effect of montelukast in children with asthma predictive ındex negative episodic viral wheezing

“…24 In an insilico study, it has been shown that montelukast has anti-viral activity by interfering with the entry of the virus into the host cell. 25 Razi et al study shows that the immunostimulant given in atopy-negative children is effective. This suggests that EVW under 5 years old may be an immune defect that is insufficient to limit viral infection.…”

Anti-SARS-CoV-2 and cytotoxic activity of two marine alkaloids from green alga Caulerpa cylindracea Sonder in the Dardanelles

“…Caulerpin and monomethyl caulerpinate were docked into two different crystal structures of the SARS-CoV-2 spike protein receptor binding domain. 42 The study revealed that both compounds could interact with the pocket of the spike protein with which ACE2 also interacts and as such interfere with the binding of the latter (Fig. 3).…”