Abstract
The current outbreak of severe acute respiratory distress syndrome (SARS) or nCOVID-19 pandemic, caused by the coronavirus-2 (CoV-2), continues to wreak havoc globally. As novel vaccines are being discovered and developed, small molecule drugs still constitute a viable treatment option for SARS-CoV-2 infections due to their advantages such as superior patient compliance for oral therapies, reduced manufacturing costs and ease of large scale distribution due to better stability and storage profiles. Discovering new drugs for SARS-CoV-2 infections is a time consuming and expensive proposition. In this regard, drug repurposing is an appealing approach which can provide rapid access to therapeutics with proven record of safety and efficacy. We investigated the drug repurposing potential of a library of dipeptidyl peptidase 4 (DPP4) inhibitors which are currently marketed for type-2 diabetes as treatment option for SARS-CoV-2 infections. These computational studies led to the identification of three marketed DPP4 inhibitors; gemigliptin, linagliptin and evogliptin as potential inhibitors of SARS-CoV-2 Mpro viral cysteine protease. In addition, our computational modeling shows that these drugs have the potential to inhibit other viral cysteine proteases from the beta coronavirus family, including the SAR-CoV Mpro and MERS-CoV CLpro suggesting their potential to be repurposed as broad-spectrum antiviral agents.
Highlights
The ongoing novel coronavirus infection or severe acute respiratory distress syndrome (SARS)-CoV-2 (COVID-19 or nCOVID-19), pandemic, has already claimed more than 1.6 million lives worldwide, and continues to spread across the world at a rapid pace [1]
We investigated the binding interactions of reversible, noncovalent dipeptidyl peptidase 4 (DPP4) inhibitors gemigliptin, linagliptin and evogliptin in the active site of another coronavirus viral cysteine protease SAR-CoV Mpro
The current SARS-CoV-2 crisis has revealed that patients with pre-existing conditions such as type-2 diabetes have a greater risk of mortality due to SARS-CoV-2 infection and that the known DPP4 inhibitor sitagliptin was shown to be effective in treating COVID-19 infections in diabetic patients, its exact mechanisms are not clearly understood [18,20,22,36]
Summary
The ongoing novel coronavirus infection or SARS-CoV-2 (COVID-19 or nCOVID-19), pandemic, has already claimed more than 1.6 million lives worldwide, and continues to spread across the world at a rapid pace [1]. Recent studies have shown that the anti-malarial drug hydroxychloroquine, the antibiotic azithromycin, antiparasitic drug ivermectin and the corticosteroid dexamethansone have the potential to reduce disease severity in patients with SARS-CoV-2 infection [2,3,4,5]. This preliminary evidence suggests that small molecule therapies hold promise in treating this global pandemic. This highlights the fact that drug repurposing or the application of known marketed drugs, to treat novel diseases such as the current SARS-CoV-2 pandemic, is a practical approach that should be thoroughly investigated. Drug repurposing approach provides billions of dollars in cost savings and can dramatically reduce the time required to launch new drugs [7]
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