Dipeptidyl peptidase-4, Dipeptidyl peptidase-8, Dipeptidyl peptidase-9 (DPP4, DPP8, DPP9)

Dipeptidyl peptidase-4, -8, and -9 are homologous serine proteases that cleave N-terminal dipeptides from regulatory peptides, often after proline residues. DPP4 is membrane-bound and a major drug target in type 2 diabetes due to its role in incretin degradation, and it modulates immune regulation and signal transduction. DPP8 and DPP9 are primarily intracellular, affecting immune signaling, apoptosis, and metabolism, and have emerging implications in cancer, fibrosis, and inflammation. Drugs developed for DPP4 must be highly selective to avoid off-target effects on DPP8/9, as inhibition of the latter can have substantial safety risks.

Other names

DPP4: CD26DPP4: dipeptidyl peptidase IVDPP4: adenosine deaminase complexing protein 2DPP8/DPP9: DPP4 activity/structure homolog (DASH) family

Inhibition of dipeptidyl peptidase activity blocks the enzymatic cleavage of circulating peptides such as incretins (notably GLP-1 for DPP4), prolonging their biological effect; in DPP8/9, inhibition influences immune cell function and cellular metabolism, sometimes via inflammasome regulation.