Exploring DPP-4: Implications in diverse diseases and structural insights for novel inhibitor design

Dipeptidyl peptidase-4 (DPP-4) is a multifaceted enzyme that orchestrates a variety of physiological and pathological processes, making it a pivotal target in the treatment of several diseases. Notably, the role of DPP-4 extends beyond its well-documented involvement in glucose metabolism and type 2 diabetes mellitus (T2DM) management, where DPP-4 inhibitors (gliptins) have gained prominence. Emerging evidence highlights its significant functions in immune regulation, cardiovascular diseases, cancer, and inflammatory disorders. Structurally, DPP-4 is a serine protease that cleaves dipeptides from the N-terminus of polypeptides, influencing the activity of numerous bioactive peptides. This review delves into the diverse roles of DPP-4 across different disease states, elucidating the mechanisms by which it influences disease progression and therapeutic outcomes. Additionally, we explore the structural intricacies of DPP-4, which have informed the design of potent and selective inhibitors. Through advanced techniques in X-ray crystallography and molecular modeling, key binding interactions and conformational changes are dissected, providing insights for the development of next-generation DPP-4 inhibitors (DPP-4Is). Furthermore, the initiative of exploring chemical space of DPP-4Is provides a novel framework for the rational design of next-generation therapeutics targeting this enzyme. Understanding the structural basis of DPP-4 inhibition not only augments the therapeutic arsenal against T2DM but also opens new avenues for treating other DPP-4-related diseases, underscoring the significance of this enzyme as a versatile therapeutic target. This effort provides insights for the development of next-generation DPP-4Is.