Dipeptidyl peptidase-4 (revision 20)
Old revision·21:07, 14 Jun 2025·EmptyingElke
| Dipeptidyl peptidase-4Serine exopeptidase | |
|---|---|
| Abbreviation | DPP-4 |
| Also known as | CD26, adenosine deaminase-binding protein |
| EC number | EC 3.4.14.5 |
| Enzymology | |
| Class | Serine protease, prolyl oligopeptidase family |
| Specificity | Cleaves X-Pro or X-Ala dipeptides from the N-terminus |
| Forms | Membrane-anchored and soluble plasma form |
| Substrates of interest | |
| GLP-1 | Half-life 1–2 min |
| GIP | Half-life ≈7 min |
| Others | Substance P, NPY, several chemokines |
| Topic infobox · conventions | |
Dipeptidyl peptidase-4 (DPP-4), also known as CD26, is a serine exopeptidase that removes the N-terminal two residues from peptides presenting proline or alanine in the second position. Both incretin hormones — Glucagon-like peptide-1 and Glucose-dependent insulinotropic polypeptide — carry alanine at position 2 and are therefore inactivated within minutes of secretion.[1]
The enzyme exists as a type II membrane protein on endothelial cells, epithelial cells and lymphocytes, and as a catalytically active soluble form in plasma. Cleavage of GLP-1 begins in the capillaries of the intestinal lamina propria, before the hormone reaches the portal vein, so that only a minority of secreted GLP-1 arrives at the systemic circulation intact.[2]
DPP-4 defines the design problem for the entire GLP-1 receptor agonist class, and also constitutes a drug target in its own right. Inhibitors of the enzyme raise endogenous incretin concentrations two- to three-fold and lower glycated haemoglobin by roughly 0.5–0.8 percentage points, an effect substantially smaller than that of receptor agonists because the ceiling is set by physiological secretion.[1]
Catalytic action and substrate range
[edit]DPP-4 cleaves the dipeptide His-Ala from the N-terminus of GLP-1(7–36)amide to yield GLP-1(9–36)amide. The truncated product binds the GLP-1 receptor with roughly two orders of magnitude lower affinity and behaves as a weak antagonist at pharmacological concentrations; whether it has independent cardiovascular activity remains an open question in the literature.[2]
The substrate range is wide. Substance P, neuropeptide Y, several chemokines and the incretins are all cleaved, and the enzyme also has non-catalytic functions as a co-stimulatory molecule on T cells and as a binding partner for adenosine deaminase. The breadth of this range is the reason inhibitor development required careful selectivity against the related enzymes DPP-8 and DPP-9.[1]
Kinetically the enzyme is efficient rather than abundant: plasma DPP-4 activity is sufficient to halve circulating intact GLP-1 in about one minute, which is why the intact fraction must be measured with an assay that distinguishes GLP-1(7–36) from GLP-1(9–36) if the measurement is to mean anything.
Evading the enzyme
[edit]Every therapeutic peptide agonist in this class solves the DPP-4 problem, and the solutions are few.
| Approach | Molecule | Modification |
|---|---|---|
| Non-natural residue at position 2 | Semaglutide | α-aminoisobutyric acid (Aib) at position 8 |
| Naturally resistant scaffold | Exenatide | Glycine at position 2 of exendin-4 |
| Steric protection by acylation | Liraglutide | C-16 diacid, albumin-bound fraction shielded |
| Fusion partner | Dulaglutide | Fc domain, plus Gly substitution |
Substitution alone is not sufficient for a long dosing interval — a DPP-4-resistant peptide is still cleared renally within hours — so the resistant residue is almost always combined with an albumin-binding or fusion strategy. Semaglutide combines both, and adds a substitution at position 34 to prevent acylation at the wrong lysine.[3]
DPP-4 inhibitors as a drug class
[edit]Sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin inhibit the enzyme competitively or, in some cases, through a covalent but reversible interaction with the catalytic serine. They raise intact GLP-1 and GIP concentrations into the low postprandial physiological range rather than the supraphysiological range achieved by injected agonists.[1]
The clinical consequences follow from that ceiling. Glycated-haemoglobin reduction is modest, weight is unchanged rather than reduced, and gastrointestinal adverse effects are uncommon — the same mechanism that limits efficacy also limits toxicity. Cardiovascular outcome trials of the class have been neutral for major adverse cardiovascular events, with a signal for heart-failure hospitalisation reported for one member.[1]
Because the inhibitors act on endogenous hormone, they are not interchangeable with receptor agonists and combining the two produces little additional benefit — receptor occupancy is already near-maximal under agonist therapy.
Analytical relevance
[edit]DPP-4 matters to anyone measuring incretin concentrations. Blood drawn without a DPP-4 inhibitor in the tube continues to degrade GLP-1 ex vivo, and comparisons between studies that did and did not add an inhibitor at collection are not meaningful. Total-GLP-1 assays that detect both intact and truncated forms give systematically higher and less interpretable numbers than intact-specific assays.[2]
See also
- Glucagon-like peptide-1
- Glucose-dependent insulinotropic polypeptide
- GLP-1 receptor agonist
- Albumin binding half-life extension
- Enteroendocrine L cell
References
- ^ a b c d e Deacon CF. "Physiology and pharmacology of DPP-4 in glucose homeostasis and the treatment of type 2 diabetes." Frontiers in Endocrinology 10:80 (2019). DOI:10.3389/fendo.2019.00080. PMID 30828317.
- ^ a b c Holst JJ. "The physiology of glucagon-like peptide 1." Physiological Reviews 87(4):1409–1439 (2007). PMID 17928588.
- ^ Knudsen LB, Lau J. "The discovery and development of liraglutide and semaglutide." Frontiers in Endocrinology 10:155 (2019). PMID 31031702.