The Leukotriene Receptor Antagonist Montelukast as a Potential COVID-19 Therapeutic.

Ludwig Aigner,Michael Studnicka,Daniela Schuster,Herbert Anton Reitsamer,Diana Marisa Bessa De Sousa,Frank Pietrantonio,Horst Zerbe,Johanna Michael

doi:10.3389/fmolb.2020.610132

Abstract

The emergence and global impact of COVID-19 has focused the scientific and medical community on the pivotal influential role of respiratory viruses as causes of severe pneumonia, on the understanding of the underlying pathomechanisms, and on potential treatment for COVID-19. The latter concentrates on four different strategies: (i) antiviral treatments to limit the entry of the virus into the cell and its propagation, (ii) anti-inflammatory treatment to reduce the impact of COVID-19 associated inflammation and cytokine storm, (iii) treatment using cardiovascular medication to reduce COVID-19 associated thrombosis and vascular damage, and (iv) treatment to reduce the COVID-19 associated lung injury. Ideally, effective COVID-19 treatment should target as many of these mechanisms as possible arguing for the search of common denominators as potential drug targets. Leukotrienes and their receptors qualify as such targets: they are lipid mediators of inflammation and tissue damage and well-established targets in respiratory diseases like asthma. Besides their role in inflammation, they are involved in various other aspects of lung pathologies like vascular damage, thrombosis, and fibrotic response, in brain and retinal damages, and in cardiovascular disease. In consequence, leukotriene receptor antagonists might be potential candidates for COVID-19 therapeutics. This review summarizes the current knowledge on the potential involvement of leukotrienes in COVID-19, and the rational for the use of the leukotriene receptor antagonist montelukast as a COVID-19 therapeutic.

Highlights

This review summarizes the current knowledge on the potential involvement of leukotrienes in COVID-19, and the rational for the use of the leukotriene receptor antagonist montelukast as a COVID-19 therapeutic
In the search for a common denominator involved in the modulation of these various aspects of COVID-19 pathology we identified leukotrienes (LTs), in particular the cysteinylleukotrienes (Cys-LTs) and their receptors as potential drug targets
The fact that CysLTs are involved in the various aspects of respiratory disease pathologies such as inflammation, thrombosis and vascular damage, and fibrotic remodeling provides a rationale for inhibition of LTs and the use of montelukast in respiratory diseases beyond asthma, for example in viral pneumonia related to SARS-CoV-2 infections

Summary

Leukotrienes and Leukotriene Receptors

LTs are eicosanoids and inflammatory mediators produced by various cell types including leukocytes. CysLTs bind to specific CysLT receptors (CysLTRs) namely, CysLTR1, CysLTR2, P2Y12, GPR99, and GPR-17 These G protein-coupled receptors are expressed on the outer membrane of a variety of cells including immune and inflammatory cells (i.e., basophils, mast cells, dendritic cells, eosinophils, monocytes/macrophages, B cells, CD4+ T cells, and to a lesser degree on neutrophils and CD8+ cells), endothelial cells and platelets (Peters-Golden and Henderson, 2007; Okunishi and Peters-Golden, 2011). P2Y12 is mainly expressed by platelets and in various other cell types including cells of the upper and lower respiratory tract, where it mediates LT-induced effects such as eosinophilic inflammation in asthma (Foster et al, 2013; Suh et al, 2016). The oxoglutarate receptor GPR99 may be activated by CysLTs in mice and in vitro, but its role in human CysLT-induced effects remains to be established (Back et al, 2014)

Cysteinyl Leukotrienes in Lung and Respiratory Disease Pathologies

Effects of Montelukast in Viral Infection and Propagation

Montelukast to Reduce Inflammation in Lung and Respiratory Diseases

Montelukast Affects Platelets and Alleviates Vascular Damages

Findings

RECENT CONCERNS ON SAFETY OF MONTELUKAST