Why GIP, GLP-1 and GHRH All Have Alanine in Position 2 (and What DPP-IV Does About It)

This article describes published laboratory science for educational purposes. It makes no claims about use in people.

Look at the first three residues of three unrelated hormones. GIP starts Tyr-Ala-Glu. GLP-1 starts His-Ala-Glu. GHRH starts Tyr-Ala-Asp. Position 2 is alanine in all three, and that is no coincidence.

The enzyme

Dipeptidyl peptidase IV (DPP-IV) clips two residues from the front of a peptide when the second residue is alanine or proline. For these hormones that means a fast switch-off, often within minutes.

How chemists fight back

• Aib at position 2: the bulky alpha-aminoisobutyric acid does not fit the enzyme. Tirzepatide-class research peptides use this idea.
• D-alanine at position 2: used in modified GRF(1-29).
• N-terminal caps: the hexenoyl group on Tesamorelin.

The pattern

Three families, one weakness, three different fixes. It is a classic case study in medicinal chemistry.

See our research-only GLP2-TZ and Tesamorelin 10mg listings. Keep reading.

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For laboratory research use only. Not for human or veterinary use, and not intended to diagnose, treat, cure or prevent any condition. This article is educational and is not medical advice.