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.