Targeted Degradation of Dipeptidyl Peptidase-4 via Proteolysis-Targeting Chimera Technology for Sustained Glycemic Control in Type 2 Diabetes - PubMed
5 hours ago
- #DPP-4
- #diabetes
- #PROTAC
- Dipeptidyl peptidase-4 (DPP-4) is a key regulator of glucose metabolism and a therapeutic target for type 2 diabetes.
- Conventional DPP-4 inhibitors like alogliptin can lead to resistance and off-target effects due to sustained exposure.
- A PROTAC (DeDPP4) was developed by conjugating alogliptin with a cereblon-recruiting E3 ubiquitin ligase ligand.
- DeDPP4 showed dose-dependent DPP-4 depletion in A549 cells, with a maximal degradation rate of >80%.
- In vivo, a single dose of DeDPP4 (10 mg/kg) provided prolonged glycemic control for over 60 hours, 5 times longer than alogliptin.
- DeDPP4 induced sustained GLP-1 elevation and improved glucose tolerance, correlating with DPP-4 degradation in liver and adipose tissues.