Source of Dipeptidyl peptidase-4

{{Infobox concept | name = Dipeptidyl peptidase-4 | subtitle = Serine 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 }} {{hatnote|For the hormones this enzyme inactivates, see [[Glucagon-like peptide-1]] and [[Glucose-dependent insulinotropic polypeptide]].}} '''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.{{r|deacon2019}} 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.{{r|holst2007}} 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.{{r|deacon2019}} == Catalytic action and substrate range == 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.{{r|holst2007}} 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.{{r|deacon2019}} 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 == 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 half-life extension|albumin-binding]] or fusion strategy. Semaglutide combines both, and adds a substitution at position 34 to prevent acylation at the wrong lysine.{{r|knudsen2019}} == DPP-4 inhibitors as a drug class == 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.{{r|deacon2019}} 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.{{r|deacon2019}} 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 == 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.{{r|holst2007}} The same consideration applies to stability work on the therapeutic peptides themselves. A DPP-4-resistant analogue is resistant to that specific enzyme, not to proteolysis in general, and stability in plasma is not evidence of stability in a reconstituted vial, where [[Deamidation|deamidation]] and [[Peptide aggregation|aggregation]] rather than proteolysis are the degradation routes that matter.{{r|usp1503}} == References == {{reflist}} <ref name="deacon2019">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.</ref> <ref name="holst2007">Holst JJ. "The physiology of glucagon-like peptide 1." ''Physiological Reviews'' 87(4):1409–1439 (2007). PMID 17928588.</ref> <ref name="knudsen2019">Knudsen LB, Lau J. "The discovery and development of liraglutide and semaglutide." ''Frontiers in Endocrinology'' 10:155 (2019). PMID 31031702.</ref> <ref name="usp1503">United States Pharmacopeia, General Chapter <1503>, ''Quality Attributes of Synthetic Peptide Drug Substances''.</ref> == See also == * [[Glucagon-like peptide-1]] * [[Glucose-dependent insulinotropic polypeptide]] * [[GLP-1 receptor agonist]] * [[Albumin binding half-life extension]] * [[Enteroendocrine L cell]] {{DEFAULTSORT:Dipeptidyl peptidase-4}} [[Category:Incretin biology]] [[Category:Receptor pharmacology]] [[Category:Pharmacokinetics]]