Pharmacology, Physiology, and Mechanisms of Action of Dipeptidyl Peptidase-4 Inhibitors

Abstract

Dipeptidyl peptidase-4 (DPP4) is a widely expressed enzyme transducing actions through an anchored transmembrane molecule and a soluble circulating protein.Both membrane-associated and soluble DPP4 exert catalytic activity, cleaving proteins containing a position 2 alanine or proline.DPP4-mediated enzymatic cleavage alternatively inactivates peptides or generates new bioactive moieties that may exert competing or novel activities.The widespread use of selective DPP4 inhibitors for the treatment of type 2 diabetes has heightened interest in the molecular mechanisms through which DPP4 inhibitors exert their pleiotropic actions.Here we review the biology of DPP4 with a focus on: 1) identification of pharmacological vs physiological DPP4 substrates; and 2) elucidation of mechanisms of actions of DPP4 in studies employing genetic elimination or chemical reduction of DPP4 activity.We review data identifying the roles of key DPP4 substrates in transducing the glucoregulatory, anti-inflammatory, and cardiometabolic actions of DPP4 inhibitors in both preclinical and clinical studies.Finally, we highlight experimental pitfalls and technical challenges encountered in studies designed to understand the mechanisms of action and downstream targets activated by inhibition of DPP4.(Endocrine Reviews 35: 992-1019, 2014) I. Introduction II.Molecular Biology of DPP4 A. Discovery, genomic organization, and superfamily of related enzymes B. Molecular function C. Regulation of DPP4 expression D. Post-translational modifications of DPP4 III.DPP4 Substrates A. Brain natriuretic peptide (BNP) B. Erythropoietin C. Eotaxin D. Gastrin-releasing peptide (GRP) E. Glucagon F. Glucagon-like peptide-1 (GLP-1) G. Glucagon-like peptide-2 (GLP-2) H. Glucose-dependent insulinotropic polypeptide (GIP) I. Granulocyte colony-stimulating factor (G-CSF) J. Granulocyte-macrophage CSF (GM-CSF) K. GHRH and IGF-1 L. High-mobility group box 1 (HMGB1) M. Macrophage-derived chemokine (MDC) N. Macrophage inflammatory protein-1 ␣ (MIP-1 ␣), chemokine (C-C motif) ligand 3-like 1 (CCL3L1), or LD78␤ O. Oxyntomodulin P. Pituitary adenylate cyclase-activating polypeptide (PACAP) Q. Neuropeptide Y (NPY) R. Peptide tyrosine tyrosine (PYY) S. Regulated on activation, normal T cell expressed and secreted (Rantes) T. Stromal cell-derived factor-1 (SDF-1) U. Substance P (SP) IV.Discovery of DPP4 as a Drug Target A. Selective DPP4 inhibitors, glucoregulatory substrates, and the treatment of type 2 diabetes B. Metabolic phenotypes in animal models of DPP4 deficiency V. Mechanism(s) of Action of DPP4 Inhibitors A. Selectivity of DPP4 inhibitors B. Mechanisms through which DPP4 inhibitors lower glucose C. Proof of concept and mechanisms for DPP4-dependent glucose control in humans