Exploring dual applications of gliptins: A potential host-targeted strategy for diabetes and COVID-19 co-morbidity

Abstract

The COVID-19 pandemic has underscored the urgent need for innovative therapeutic strategies, particularly for vulnerable populations such as individuals with Type 2 diabetes mellitus (T2DM), who face heightened risks of severe complications. Gliptins, widely used as dipeptidyl peptidase-4 (DPP4) inhibitors in T2DM management, have emerged as promising candidates for therapeutic repurposing against SARS-CoV-2 infection. This study hypothesizes that gliptins can serve as dual-purpose therapeutic agents, targeting both T2DM and SARS-CoV-2, by leveraging their inhibitory effects on host receptors such as DPP4 and ACE2, which are implicated in viral entry and pathogenesis. There is also an established association between the increased COVID-19 risk with the hyperglycemia through SLC5A receptor variants. Preliminary evidence from in silico analyses supports this hypothesis, demonstrating strong binding affinities of gliptins, particularly linagliptin and alogliptin, to key receptors involved in SARS-CoV-2 infection. This dual targeting potential suggests that gliptins could hypothetically reduce viral replication while simultaneously managing hyperglycemia. To further validate this hypothesis, molecular dynamics simulations, followed by in vitro and in vivo studies, are proposed. The ultimate goal is to evaluate the clinical utility of gliptins, either as standalone treatments or in combination with other therapies, in managing COVID-19 among diabetic patients. This proposed therapeutic strategy not only addresses the immediate challenges of treating COVID-19 in patients with comorbid T2DM but also offers a robust host-targeted approach that is resilient to viral mutations. If successful, it could redefine the management of comorbid conditions in infectious disease scenarios, offering a sustainable and broadly applicable solution to future public health crises.