Leukotrienes, a potential target for Covid-19

Abstract

Repositioning of clinically approved drugs that may reduce the severity, hospitalization events, and time of recovery from SARS-CoV2 infection is a global health priority. Clinical reports of drug effects and lung pathology are providing insight into the pathogenesis of Covid-19, and comparison of these findings with our knowledge of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) can be used to develop rational hypotheses to prioritize clinical studies of available therapeutics. Recently, Cao and colleagues [1] investigated the addition of a lopinavir-ritonavir regimen to standard of care, which previously showed promising activity in an open-label clinical study of patients affected by SARS [2]. However, lopinavir-ritonavir therapy did not confer any clinical benefit for patients with Covid-19, even when patients received glucocorticoids as a supportive drug [1]. Several agents, including remdesivir and chloroquine/hydroxychloroquine alone or in combination with azithromycin, were tested as potential treatment for Covid-19 patients, however available data are still not sufficient to delineate a definitive therapeutic approach [3-5]. A relevant debate was ongoing concerning the use of non-steroidal anti-inflammatory drugs (NSAIDs) to treat patients with Covid-19 [6,7]. Following a survey by the French National Agency for Medicines and Health Products Safety (ANSM), US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are investigating a potential correlation between NSAIDs and increased severity of Covid-19 symptomatology, supporting possible negative effects of these drugs to exacerbate Covid-19-related viral and bacterial pulmonary infections, leading to increased hospitalization rates and poor health outcomes. Although no clinical findings were previously reported to suggest any potential risk to use NSAIDs to treat patients with SARS or MERS, NSAID-induced down-regulation of prostaglandins and thromboxanes through cyclooxygenase (COXs) inhibition shifts metabolism of arachidonic acid toward the lipoxygenase (LOX) pathway, resulting in a net increase in leukotrienes production. Of note, leukotrienes are potent chemotactic and

Montelukast and Coronavirus Disease 2019: A Scoping Review

“…41 Six articles (16.7%) proposed MK as a potential treatment in SARS-CoV-2 positive patients through altering NF-kB signaling pathway, targeting the increased vascular permeability, suppressing recruitment of the innate immune response as well as bronchoconstriction resulted from cytokine release and also lung injury. 14,15,[29][30][31]43 MK was evaluated as the only applied medicine in four out of six surveys. [29][30][31]43 However, the combination of MK with zileuton controlled-release (CR) in one study and MK with levocetirizine in another survey was suggested to be beneficial in COVID-19 patients.…”

“…14,15,[29][30][31]43 MK was evaluated as the only applied medicine in four out of six surveys. [29][30][31]43 However, the combination of MK with zileuton controlled-release (CR) in one study and MK with levocetirizine in another survey was suggested to be beneficial in COVID-19 patients. 14,15 Eighteen studies (50%) involved confirmed SARS-CoV-2 positive patients (Table 2) comprising two studies that detected high levels of leukotrienes (LTs) in the sera from COVID-19 patients, 44,45 indicating a therapeutic role for MK as an effective leukotriene inhibitor.…”

Screening Anti-inflammatory, Anticoagulant, and Respiratory Agents for SARS-CoV-2 3CL^pro Inhibition from Chemical Fingerprints Through a Deep Learning Approach

“…It was pointed out as a possible SARS-CoV-2 M pro inhibitor in a molecular-docking virtual screening 33 and as an adjuvant treatment promotes the recovery of all types of COVID-19 and further reduces the mortality rate of elderly and those with comorbidities in a clinical study 34 . The NSAID fenoprofen calcium inhibits both isozymes of COX and activates both peroxisome proliferator activated receptors 35 ; therefore, it may downregulate leukotriene B4 production and thereby interfere with the leukotriene pathway of inflammatory exacerbation, which has been demonstrated to mediate lung injury in several diseases [35][36][37] .…”

Cancer vs. SARS-CoV-2 induced inflammation, overlapping functions, and pharmacological targeting

“…In the case of SARS-CoV-2 infection, leukotrienes are not paid attention to (Funk and Ardakani 2020 ). Since leukotriene inhibitors are used in anti-cancer treatments (Steele et al 1999 ; Werz and Steinhillber 2006 ), they are also suggested for COVID-19 patients (Citron et al 2020 ; Funk and Ardakani 2020 ). However, it has been recommended that ACE inhibitors in combination with NSAIDs increase the risk of kidney injury, yet, sufficient scientific evidence has not been established for this (Zolk et al 2020 ).…”