Montelukast drug activity and potential against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)

Copertino, Dennis C.; Duarte, Rodrigo R.R.; Powell, Timothy R.; Rougvie, Miguel de Mulder; Nixon, Douglas F.

doi:10.1002/jmv.26299

Cited by 30 publications

(37 citation statements)

References 14 publications

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“…Amongst selected candidates identified through the connectivity mapping analyses, we sought to infer whether they were predicted to bind to key SARS-CoV-2 enzymes using a chemoinformatic approach (as previously, e.g., (Copertino et al 2021 a)), to provide an indication of potential multi-modal effects against COVID-19. We performed molecular docking simulations on the RNA-dependent RNA polymerase (RdRp) (Protein Data Bank ID: 6M71), and the main protease (Mpro) (PDB ID: 6Y2E) of SARS-CoV-2, using default settings in the Protein–Ligand ANT System (PLANTS) (Korb et al 2009 ), as described elsewhere (Copertino et al 2021 b). The ligand docking sites were specified, respectively, as the catalytic sites determined by Zhang et al ( 2020 a) (Gln189) and Gao et al ( 2020 ) (Asp623), using an estimated radius of 10 Å around the specified residues.…”

Section: Methodsmentioning

confidence: 99%

Identifying FDA-approved drugs with multimodal properties against COVID-19 using a data-driven approach and a lung organoid model of SARS-CoV-2 entry

Duarte

Copertino

Íñiguez

et al. 2021

Mol Med

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Background Vaccination programs have been launched worldwide to halt the spread of COVID-19. However, the identification of existing, safe compounds with combined treatment and prophylactic properties would be beneficial to individuals who are waiting to be vaccinated, particularly in less economically developed countries, where vaccine availability may be initially limited. Methods We used a data-driven approach, combining results from the screening of a large transcriptomic database (L1000) and molecular docking analyses, with in vitro tests using a lung organoid model of SARS-CoV-2 entry, to identify drugs with putative multimodal properties against COVID-19. Results Out of thousands of FDA-approved drugs considered, we observed that atorvastatin was the most promising candidate, as its effects negatively correlated with the transcriptional changes associated with infection. Atorvastatin was further predicted to bind to SARS-CoV-2’s main protease and RNA-dependent RNA polymerase, and was shown to inhibit viral entry in our lung organoid model. Conclusions Small clinical studies reported that general statin use, and specifically, atorvastatin use, are associated with protective effects against COVID-19. Our study corroborrates these findings and supports the investigation of atorvastatin in larger clinical studies. Ultimately, our framework demonstrates one promising way to fast-track the identification of compounds for COVID-19, which could similarly be applied when tackling future pandemics.

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Section: Methodsmentioning

confidence: 99%

Identifying FDA-approved drugs with multimodal properties against COVID-19 using a data-driven approach and a lung organoid model of SARS-CoV-2 entry

Duarte

Copertino

Íñiguez

et al. 2021

Mol Med

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“…Our search included 11 (30.5%) in silico studies. A total of 8 out of 11 (72.7%) considered MK as a potential main protease (Mpro) inhibitor of SARS-CoV-2 21,23,[36][37][38][39][40][41] and two (18.2%) expressed MK's ability to dock the RNA dependent RNA polymerase (RdRp) site of SARS-CoV-2. 21,42 Spike glycoprotein site (S1 subunit) 23 and papain-like protease (PLpro) 22 were the other connection sites, each reported in one study.…”

Section: Resultsmentioning

confidence: 99%

“…A total of 8 out of 11 (72.7%) considered MK as a potential main protease (Mpro) inhibitor of SARS-CoV-2 21,23,[36][37][38][39][40][41] and two (18.2%) expressed MK's ability to dock the RNA dependent RNA polymerase (RdRp) site of SARS-CoV-2. 21,42 Spike glycoprotein site (S1 subunit) 23 and papain-like protease (PLpro) 22 were the other connection sites, each reported in one study. One of the articles introduced MK as an effective drug on mutated SARS-CoV-2, mostly against A191V site mutation within the SARS-CoV-2 Mpro.…”

Section: Resultsmentioning

confidence: 99%

“…20 Interestingly, Copertino D.C Jr et al, reported that MK is likely to dock to the both Mpro and RNA-dependent RNA polymerase (RdRp) site of SARS-CoV-2. 21 Spike glycoprotein (S1 subunit) and PLpro were also the other connection sites of MK introduced by Maffucci I. and A. Contini and Kumar S. et al 22,23 LTs have already been shown to be involved in acute respiratory distress syndrome (ARDS) and increasing vascular permeability. 24,25 Considering the significantly higher levels of LTs in the COVID-19 patients' sera, an inhibitory role for MK against COVID-19 could be assumed.…”

Section: Discussionmentioning

confidence: 99%

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Montelukast and Coronavirus Disease 2019: A Scoping Review

Sharifinejad¹,

Sharafian²,

Salekmoghadam³

et al. 2021

IJAAI

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Coronavirus disease 2019 (COVID-19) is an emerging worldwide issue, that has affected a large number of people around the world. So far, many studies have aimed to develop a therapeutic approach against COVID-19. Montelukast (MK) is a safe asthma controller drug, which is considered as a potential antiviral drug for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This review has a systematic approach to investigate the reports on the use of MK as a part of treatment or a prophylactic agent in COVID-19. The search was conducted in PubMed, Web of Science, and Scopus databases and yielded 35 studies containing the influence of MK on SARS-CoV-2. Ultimately, MK appears to be worth being used as an adjuvant therapeutic and prophylactic drug against SARS-CoV-2. Nevertheless, more clinical trials are required to accurately investigate its effectiveness.

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“…In addition, activation of LTs in SARS-CoV-2 infections is linked to a high level of pro-inflammatory cytokines and poor clinical outcomes in patients with severe Covid-19. Thereby, the inhibition of LT pathway may mitigate immune response, pulmonary inflammation and Covid-19 severity ( Copertino et al, 2021 ). Hence, Cys-LTR1 antagonists, like montelukast and zafirlukast, able to block the synthesis and release of pro-inflammatory cytokines and production of reactive oxygen species via inhibition of nuclear factor kappa-B (NF-κB) and mitogen activated protein kinase (MAPK) P38 of activated macrophages may reduce the likelihood of develop different inflammatory disorders ( Citron et al, 2020 ).…”

Section: Montelukast and Pulmonary Manifestations Of Covid-19mentioning

confidence: 99%

Role of leukotriene pathway and montelukast in pulmonary and extrapulmonary manifestations of Covid-19: The enigmatic entity

Al-Kuraishy

Al-Gareeb

Almulaiky

et al. 2021

European Journal of Pharmacology

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Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the responsible agent for the coronavirus disease 2019 (Covid-19), has its entry point through interaction with angiotensin converting enzyme 2 (ACE2) receptors, highly expressed in lung type II alveolar cells and other tissues, like heart, pancreas, brain, and vascular endothelium. This review aimed to elucidate the potential role of leukotrienes (LTs) in the pathogenesis and clinical presentation of SARS-CoV-2 infection, and to reveal the critical role of LT pathway receptor antagonists and inhibitors in Covid-19 management. A literature search was done in PubMed, Scopus, Web of Science and Google Scholar databases to find the potential role of montelukast and other LT inhibitors in the management of pulmonary and extra-pulmonary manifestations triggered by SARS-CoV-2. Data obtained so far underline that pulmonary and extra-pulmonary manifestations in Covid-19 are attributed to a direct effect of SARS-CoV-2 in expressed ACE2 receptors or indirectly through NF-κB dependent induction of a cytokine storm. Montelukast can ameliorate extra-pulmonary manifestations in Covid-19 either directly through blocking of Cys-LTRs in different organs or indirectly through inhibition of the NF-κB signaling pathway.

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Montelukast drug activity and potential against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)

Cited by 30 publications

References 14 publications

Identifying FDA-approved drugs with multimodal properties against COVID-19 using a data-driven approach and a lung organoid model of SARS-CoV-2 entry

Identifying FDA-approved drugs with multimodal properties against COVID-19 using a data-driven approach and a lung organoid model of SARS-CoV-2 entry

Montelukast and Coronavirus Disease 2019: A Scoping Review

Role of leukotriene pathway and montelukast in pulmonary and extrapulmonary manifestations of Covid-19: The enigmatic entity

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