Dipeptidyl peptidase-4 recognises peptides that carry an alanine or a proline in the second position and cleaves the dipeptide at the N-terminal end. For incretins that cut is fatal: GLP-1 and GIP lose their ability to activate the receptor.
The enzyme sits on the surface of many cells and circulates in plasma, so it acts very quickly. There are two strategies against it. One is to inhibit it with drugs (the “gliptins”), which prolongs the effect of the body's own incretins. The other is to design resistant analogues: semaglutide replaces the alanine at position 2 with Aib (aminoisobutyric acid), a non-natural amino acid DPP-4 does not recognise.
The same problem affects other peptides: natural GHRH is also a DPP-4 substrate, and analogues such as tesamorelin or CJC-1295 carry N-terminal modifications to resist it.
Behind almost every incretin and GHRH analogue there is a modification designed against DPP-4. Recognising it helps explain why their sequence differs from the natural hormone in the first positions.
Related terms
Learn it in depth at the Peptide University
- Pharmacokinetics: ADME and parameters · Module 2
- Chemical modifications: from the natural sequence to the analog · Module 1
- Half-life engineering · Module 2
- Incretin physiology · Module 3
- Pharmacology of agonists: single, dual and triple · Module 3
Related catalogue compounds
Definition for educational and scientific purposes. It is not medical advice or a recommendation for use. NeoPeptidos products are sold labelled for research use only (RUO).