DPP-4 (Dipeptidyl-Peptidase 4, also called CD26 or ADA-binding protein, EC 3.4.14.5) is a type II transmembrane serine protease ubiquitously expressed (intestinal, renal epithelia, vascular endothelium, T lymphocytes, hepatocytes), with a circulating soluble form released by ADAM17/metalloprotease cleavage. It specifically cleaves the Xaa-Pro or Xaa-Ala N-terminal dipeptide (with Pro or Ala at position 2) of peptides and proteins, exposing a new N-terminus generally biologically inactivated.
Physiological substrates. DPP-4 is responsible for rapid inactivation of many bioactive peptides: GLP-1 (7-37 → 9-37, half-life <2 min), GIP (1-42 → 3-42, half-life ~7 min), GHRH (1-44 → 3-44, half-life ~7 min), GRP, substance P, neuropeptide Y (NPY 1-36 → 3-36, Y1→Y2/Y5 switch), BNP/ANP, PYY (1-36 → 3-36, conversion to more active PYY3-36), chemokines (CXCL10, CCL5/RANTES, IP-10) and haematopoietic factors (SDF-1α/CXCL12, G-CSF). This activity regulates insulin secretion, lymphocyte chemotaxis and the GH axis.
Therapeutic inhibitors. Gliptins (competitive DPP-4 inhibitors) constitute a major class of oral antidiabetics: sitagliptin (Januvia®, Merck, 2006), vildagliptin (Galvus®, Novartis), saxagliptin (Onglyza®, BMS), linagliptin (Tradjenta®, Boehringer), alogliptin (Nesina®, Takeda). They increase endogenous GLP-1 and GIP half-life by 2-3x, improving HbA1c by 0.5-0.8% with favourable safety profile (no weight gain, rare hypoglycaemia, resolved pancreatitis controversy).
Resistance strategy in peptide design. To bypass DPP-4 inactivation of therapeutic peptides, three strategies are used: (1) Pro2→Aib substitution (exenatide, semaglutide, tirzepatide), (2) Ala2→D-Ala or Gly substitution (CJC-1295, liraglutide), (3) extended lipid acylation + albumin binding sterically blocking DPP-4 access. These modifications extend plasma half-life from minutes to days and enable weekly administration (semaglutide, tirzepatide, retatrutide).
Décryptez la caractérisation complète d'un peptide : RP-HPLC préparative et analytique, LC-MS haute résolution Orbitrap/QTOF, RMN 2D (COSY/TOCSY/NOESY), dégradation d'Edman, cartographie peptidique MS/MS, dichroïsme circulaire. Les 10 techniques qui séparent un peptide research-grade d'un peptide douteux, avec seuils de détection et stratégie de QC.
Maitrisez les mecanismes qui detruisent vos peptides : oxydation Met, deamidation Asn, hydrolyse, aggregation. Protocoles de lyophilisation, conditions de stockage, reconstitution optimale et QC shelf-life. Le pilier technique que tout laboratoire doit integrer pour garantir l'integrite de ses peptides en recherche exploratoire.
Structure, mécanisme triple agoniste, pharmacocinétique, programme TRIUMPH (1-4, Obesity, HFpEF, MASH), comparaison versus semaglutide et tirzepatide, protocoles de reconstitution RUO, stabilité et perspectives réglementaires. Le pilier scientifique de référence sur le retatrutide.