montelukast and Coronavirus-Infections

Middle East Respiratory Syndrome (MERS) is a respiratory disease caused by a coronavirus (MERS-CoV). Since its emergence in 2012, nosocomial amplifications have led to its high epidemic potential and mortality rate of 34.5%. To date, there is an unmet need for vaccines and specific therapeutics for this disease. Available treatments are either supportive medications in use for other diseases or those lacking specificity requiring higher doses. The viral infection mode is initiated by the attachment of the viral spike glycoprotein to the human Dipeptidyl Peptidase IV (DPP4). Our attempts to screen antivirals against MERS led us to identify montelukast sodium hydrate (MSH), an FDA-approved anti-asthma drug, as an agent attenuating MERS-CoV infection. We showed that MSH directly binds to MERS-CoV-Receptor-Binding Domain (RBD) and inhibits its molecular interaction with DPP4 in a dose-dependent manner. Our cell-based inhibition assays using MERS pseudovirions demonstrated that viral infection was significantly inhibited by MSH and was further validated using infectious MERS-CoV culture. Thus, we propose MSH as a potential candidate for therapeutic developments against MERS-CoV infections.

Topics: Acetates; Animals; Anti-Asthmatic Agents; Antiviral Agents; Carrier Proteins; Chlorocebus aethiops; Coronavirus Infections; Cyclopropanes; Cytochrome P-450 CYP1A2 Inducers; Dipeptidyl Peptidase 4; Drug Repositioning; HEK293 Cells; Humans; Leukotriene Antagonists; Middle East Respiratory Syndrome Coronavirus; Quinolines; Receptors, Virus; Spike Glycoprotein, Coronavirus; Sulfides; Vero Cells; Virus Internalization

It has been hypothesized that Montelukast, a cysteinyl leukotriene (cysLT) receptor antagonist, with effects of anti-inflammatory, suppress oxidative stress and reduce affect cytokine production, may limited progression of the disease on COVID-19 infection.

Topics: Acetates; Anti-Inflammatory Agents; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cyclopropanes; Cytokines; Disease Progression; Humans; Inflammation; Oxidative Stress; Pandemics; Pneumonia, Viral; Quinolines; Receptors, Leukotriene; SARS-CoV-2; Sulfides

Topics: Acetates; Adult; Albuterol; Anti-Asthmatic Agents; Asthma; Betacoronavirus; Black or African American; Coronavirus Infections; COVID-19; Cyclopropanes; Dyspnea; Female; Histamine Antagonists; Humans; Lung; Male; Pandemics; Pneumonia, Viral; Quinolines; SARS-CoV-2; Severity of Illness Index; Sulfides

It is widely believed that infection with the SARS-CoV-2 virus triggers a disproportionate immune response which causes a devastating systemic injury, particularly in individuals with obesity, itself a chronic, multi-organ inflammatory disease. Immune cells accumulate in visceral adipose tissue and together with paracrine adipocytes release a wide range of biologically active cytokines (including IL-1β, IL5, IL6 and IL8) that can result in both local, pulmonary and systemic inflammation. A more intense 'cytokine storm' is postulated as the mechanism behind the extreme immune response seen in severe COVID-19. It is striking how dangerous the combination of obesity and COVID-19 is, resulting in a greater risk of ICU admission and a higher mortality. Furthermore, patients from a BAME background appear to have increased mortality after SARS-CoV-2 infection; they also have a higher prevalence of central obesity and its metabolic complications. In the absence of an effective vaccine, the therapeutic potential of immune-modulating drugs is a priority, but the development of new drugs is expensive and time-consuming. A more pragmatic solution would be to seek to repurpose existing drugs, particularly those that might suppress the heightened cytokine activity seen in obesity, the major risk factor for a poor prognosis in COVID-19. Montelukast is a cysteinyl leukotriene receptor antagonist licensed to treat asthma and allergic rhinitis. It has been shown to diminish pulmonary response to antigen, tissue eosinophilia and IL-5 expression in inflammatory cells. It has also been shown to decrease elevated levels of IL-1β and IL8 in humans with viral upper respiratory tract infections compared with placebo-treated patients. In addition, in silico studies have demonstrated a high binding affinity of the montelukast molecule to the terminal site of the virus's main protease enzyme which is needed for virus RNA synthesis and replication. Montelukast, which is cheap, safe and widely available would appear to have the potential to be an ideal candidate drug for clinical trials, particularly in early stage disease before irreparable tissue damage has already occurred. HYPOTHESIS: Through a direct anti-viral effect, or by suppression of heightened cytokine release in response to SARS-CoV-2, montelukast will reduce the severity of immune-mediated multiorgan damage resulting from COVID-19, particularly in patients with central obesity and metabolic syndrome.

Topics: Acetates; Antiviral Agents; Betacoronavirus; Coronavirus 3C Proteases; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cyclopropanes; Cysteine Endopeptidases; Cytokine Release Syndrome; Drug Repositioning; Humans; Immunologic Factors; Inflammation; Leukotriene Antagonists; Obesity; Pandemics; Pneumonia, Viral; Quinolines; SARS-CoV-2; Sulfides; Viral Nonstructural Proteins

Topics: Acetates; Adrenergic beta-2 Receptor Antagonists; Amoxicillin-Potassium Clavulanate Combination; Anti-Asthmatic Agents; Antibodies, Monoclonal, Humanized; Asthma; Azithromycin; Betacoronavirus; Budesonide; Convalescence; Coronavirus Infections; COVID-19; Cyclopropanes; Eosinophils; Female; Humans; Hydroxychloroquine; Ipratropium; Male; Middle Aged; Pandemics; Pneumonia, Viral; Quinolines; SARS-CoV-2; Sulfides; Treatment Outcome

Topics: Acetates; Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Betacoronavirus; Coronavirus Infections; COVID-19; Cyclopropanes; Cytokine Release Syndrome; Humans; Hydroxyurea; Immunologic Factors; Indoles; Leukotrienes; Pandemics; Phenylcarbamates; Pneumonia, Viral; Quinolines; SARS-CoV-2; Severity of Illness Index; Sulfides; Sulfonamides; Tosyl Compounds