Dipeptidyl Peptidase-4 (DPP-4)
An enzyme that rapidly degrades the incretin hormones GLP-1 and GIP by cleaving two amino acids from their N-terminus, giving natural GLP-1 a half-life of only 1-2 minutes. GLP-1 receptor agonists are structurally modified to resist DPP-4 cleavage, enabling once-weekly or once-daily dosing.
Technical Context
DPP-4 (CD26) is a serine protease expressed on cell surfaces (particularly in the endothelium, kidney, liver, and immune cells) and circulating as a soluble form in plasma. It cleaves a dipeptide from the N-terminus of peptides with alanine or proline at position 2 — GLP-1(7-36) is cleaved to inactive GLP-1(9-36) and GIP(1-42) to inactive GIP(3-42). This cleavage occurs within 1-2 minutes of secretion. Two therapeutic strategies address DPP-4: oral DPP-4 inhibitors (sitagliptin, saxagliptin — small molecules that block the enzyme, extending endogenous GLP-1/GIP activity) and injectable GLP-1 receptor agonists (structurally modified to resist DPP-4 cleavage entirely). GLP-1 RAs produce much larger pharmacological effects because they achieve supraphysiological receptor activation.