Targeted Degradation of Dipeptidyl Peptidase-4 via Proteolysis-Targeting Chimera Technology for Sustained Glycemic Control in Type 2 Diabetes

Dipeptidyl peptidase-4 (DPP-4), a key regulator of glucose metabolism that cleaves glucagon-like peptide-1 (GLP-1), is a critical therapeutic target for type 2 diabetes. Conventional DPP-4 inhibitors like alogliptin act through competitive active-site inhibition, requiring sustained exposure, which can lead to resistance and off-target effects. Here, we leveraged proteolysis-targeting chimera (PROTAC) technology to develop a heterobifunctional DPP-4 degrader. The PROTAC (DeDPP4) was synthesized by conjugating alogliptin, a high-affinity DPP-4 ligand, with a cereblon (CRBN)-recruiting E3 ubiquitin ligase ligand. The DeDPP4 demonstrated a dose-dependent DPP-4 depletion effect in A549 cells, with a maximal degradation rate of >80%. In an in vivo experiment, a single administration of the DeDPP4 (10 mg/kg) elicited prolonged glycemic control, maintaining reduced blood glucose levels over 60 h, which was 5 times that of alogliptin. The DeDPP4 induced sustained GLP-1 elevation and enhanced glucose tolerance, correlating with DPP-4 degradation in liver and adipose tissues.