Montelukast has been used widely in treatment of Asthmatic patients since 1998 in the United States 1. The mechanism of action of Montelukast has been due to its antagonistic effects on the leukotriene D4 receptors which relaxes smooth muscles in lungs and reduces inflammation 1.
World was taken by surprise when a novel Coronavirus related illness broke out in late 2019 in Wuhan province of China and later was declared as a Pandemic due to its global impact by World Health Organization (WHO)2. Since then the illness has impacted the world which have been unprecedented with over a million people who have been affected. The mortality rate was reported to be 4% in China but it is observed to vary in different countries3.
The current literature in relation to the immunological response in SARS-CoV-2 is scarce. However, studies done in the past on Coronoviruses (CoVs) in particular SARS-CoV and MERS-CoV do bridge this knowledge gap. The host immune system after the viral entry recognizes this by pattern recognition receptors (PRRs) that include Toll like receptors (TLR), C-type lectin-like receptors, RIG-1 like receptors (RLR) AND NOD-like receptor (NLR)4. There are different pathways through which the virus induces expression of inflammatory markers that limits spread and accelerates macrophage phagocytosis of the viral antigens3, 4. The viral N-Protein of SARS-CoV is linked to protect the virus against this immune assault 4. CD4+T and CD8+ T cells play an important role in the host adaptive immune response whereby CD4+T cells stimulate the B-cells to in producing antibodies while CD8+T cells directly kill the virus-infected cells. The free radical injury to various organs is as a result of the hyper-exaggerated immune response specially lungs and may result in multi-organ failure and death5. This immune cascade is also termed as “cytokine storm”.
The main difference from autopsy findings from other related diseases with cytokine storm was destruction of lymphoid tissue in SARS-COV-2 6. Low CD4+T cells and CD8+T cells on immunohistochemical staining were observed 6. The characteristic finding in the lungs showed diffuse alveolar damage and infiltration of monocytes and macrophages 6.
Cytokine storm was the term first used in 1993 in an article on graft-versus host disease but since 2005 after avian H5N1 influenza it has been widely used 7. It has also been reported with infections related to cytomegalovirus, Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis, group A streptococcus, influenza virus, variola virus, and severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 8-12.
The SARS-cov-2 iS known to activate the innate and adaptive immune response by binding to ACE2 receptor 13. The underlying systemic response in cytokine storm results in release of TNFα, IL-1β, IL-2, IL-6, IFNα, IFNβ, IFNγ, and MCP-1 which result in production of free radicals from the immune cells causing hyper-permeability, end-organ damage and acute respiratory distress syndrome (ARDS) 14.
Montelukast Mechanism of Action:
Montelukast is proposed to potentiate its effects through two probable mechanisms:
1. Its effect in preventing the cytokine storm by modulating the immune response
Montelukast acts on cysteinyl leukotriene 1 (CysLT1) receptor inhibiting tracheal contraction by inhibiting leukotriene D4 and E4 15, 16. Leukotrienes are proinflammatory cytokines which that are produced as a result of 5-Lipoxygenase pathway (5-LO) pathway 17. The receptors for Leukotrienes are found in airways which bring about changes in relation to inflammation and spasm. Montelukast binds to these receptor sites to inhibit the action of proinflammatory cytokines 18, 19, 20.
In a septic shock model Montelukast was found to reduce the mortality by reducing the levels of TNF-α and IL-6 levels 21. It increased the levels of lipid peroxidase and myeloperoxidase activity in lungs, liver and kidney 21. This in turn protected against multiple organ failure secondary to systemic inflammatory response 21.
The high dose administration of Montelukast was also found in asthmatic patients to mediate the levels of proinflammatory cytokines IL-6, TNFα and MCP-1 through the inhibition of NF- ƙB activation 22.
2. The direct effect on the virus which is explored using the computational docking.
The molecular formula for Montelukast is C35H36ClNO3S it belongs the quinolone group of compounds, monocarboxylic acid and an aliphatic sulphide as shown in Figure.1. It has a molecular weight of 586.2 g/mol with a hydrogen bond donor count of 2, hydrogen acceptor count of 5, rotatable bond count of 12 the topological polar surface area of 95.7 Å² 23.
Computational Docking on potential viral main protease inhibitor site:
During the current SARS-CoV-2 pandemic molecular docking techniques have taken a pivotal role in generating potential treatments. In order to find the most suitable drug for a given receptor, we usually use a computation method called docking by virtue of which we get to position a given drug in a given receptor site and calculate the binding affinities between the drug and the receptor pocket.