Drug Repurposing: Dipeptidyl Peptidase IV (DPP4) Inhibitors as Potential Agents to Treat SARS-CoV-2 (2019-nCoV) Infection.

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.

Interactions of polyunsaturated fatty acids with amyloid peptides Aß40 and Aß42.

Polyunsaturated fatty acids (PUFAs) are reported to exert beneficial effects in Alzheimer's disease. Some PUFAs are known to reduce amyloid-beta (Aß) toxicity by promoting its degradation and clearance. Studies on the direct interactions of PUFAs with Aß peptides are limited and contradictory. In this study, we report the interactions of fatty acids docosahexaenoic acid (DHA), eicosatetraenoic acid (EPA), α-linolenic acid (ALA), arachidonic acid (ARA), linoleic acid (LNA) and oleic acid (OA) with Aß peptides by carrying out fluorescence based aggregation kinetic experiments, transmission electron microscopy and molecular docking studies. Our investigations demonstrate that all the fatty acids tested exhibit anti-aggregation properties by preventing both Aß40 and Aß42 fibrillogenesis (∼16-84% inhibition). OA and DHA were identified as excellent inhibitors of Aß40 or Aß42 fibrillogenesis respectively (∼84% and 81% inhibition at 25 µM). Molecular docking studies conducted, using the dimer and oligomer models of Aß40 peptide, suggest that these fatty acids interact in the aggregation prone Phe19-Ala21 and the ß-turn region (Asp23-Lys28) whereas a similar study with Aß42 dimer and oligomer models, indicate that the fatty acids were oriented in a hydrophobic region (Gln15, Leu16, Leu17 and Leu34). These results, suggest that DHA, EPA, ALA, ARA, LNA and OA are capable of directly interacting with both Aß40 and Aß42 peptides. These studies will have implications in developing potential therapeutics for Alzheimer's disease.