Diabetes mellitus (DM) poses a significant public health challenge, impacting roughly 10 % of the population. Many countries in the world are on the verge of facing a global diabetes “epidemic” [[1], [2], [3], [4]]. The long-term effects of diabetes, including myocardial infarction, blindness, diabetic nephropathy, and amputations, inflict considerable distress on individuals. Diabetes mellitus is classified into two major categories named Type 1 and Type 2 diabetes mellitus [[5], [6], [7]]. Type 1 diabetes mellitus (T1DM) [6] results from the autoimmune destruction of insulin-producing β cells in the pancreas, whereas type 2 diabetes mellitus (T2DM) is primarily linked to obesity. It is marked by impaired insulin secretion along with insulin resistance [7,8]. Globally millions of people suffer from T2DM. Currently, more than 465 million adults worldwide are affected by it, and this number is projected to rise to 700 million by 2045 [9] [1,10,11]. Researchers have explored the pathophysiology of T2DM with the aim of developing more effective treatments [5]. This has led to some promising new drugs called DPP-4 inhibitors (DPP-4Is) [[12], [13], [14], [15]].
DPP-4 is a widely distributed enzyme found on endothelial and epithelial cells. It disrupts the interaction between incretins and their receptors by cleaving two amino acids from the N-terminal end of the incretins. DPP-4Is enhanced metabolic regulation in patients with T2DM and achieved significant long-term reductions in HbA1c levels [13,[15], [16], [17], [18], [19], [20]]. Variations in the degree and duration of DPP-4 inhibition can significantly influence clinical outcomes in lowering HbA1c levels [9]. Additionally, safety and tolerability concerns related to DPP-4 activity may also impact its overall efficacy [21]. The past 25 years have witnessed a remarkable journey for DPP-4Is, from a bold idea to a widely embraced therapeutic approach [10,13,[15], [16], [17], [18],20,22].
DPP-4Is are a class of orally administered, well-tolerated compounds that specifically block the enzymatic activity of DPP-4 [23]. The chemical diversity of DPP-4Is may lead to differences in biotransformation and excretion, which can affect their therapeutic effectiveness and safety profiles. Glucagon-like peptide-1 (GLP-1) is an incretin hormone released by intestinal endocrine cells in response to food intake. Its key function is to stimulate insulin secretion from pancreatic beta cells and simultaneously suppress glucagon production [24]. Additionally, DPP-4Is may pose a risk of compound-specific toxicity and affect the pharmacotherapy of the parent drug and its metabolites, potentially leading to unintended or off-target side effects. Many research laboratories have actively focused on DPP-4, which has become a promising approach for treating T2DM [25,26].
The role of DPP-4 goes beyond regulating blood sugar, with research revealing its potential use in a range of other diseases. Therefore, understanding the involvement of DPP-4 in different pathological conditions can provide new insights into its therapeutic potential. This review highlights the multifaceted roles of DPP-4 in glucose metabolism, immune regulation, cardiovascular diseases, cancer, and inflammation. It emphasizes the structural insights into DPP-4, which can guide the design of promising inhibitors. The discussion also includes information on docking studies and pharmacokinetics to explore key binding interactions and conformational changes. These insights aim to enhance therapeutic strategies for T2DM and pave the way for developing novel inhibitors targeting DPP-4.
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