Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease?

Dipeptidyl peptidase (DPP)-4 is a member of the S9b serine protease family, which also includes DPP8 and DPP9. DPP4 cleaves a number of regulatory factors, including chemokines and growth factors. DPP4 inhibitors have recently emerged as an effective treatment option for type 2 diabetes. Early in vitro studies demonstrated that DPP4 inhibitors inhibit T-cell proliferation and cytokine production, leading to their investigation in numerous pre-clinical models of inflammatory diseases, including arthritis, multiple sclerosis and inflammatory bowel disease. Recent data suggest that the early DPP4-specific inhibitors might also bind DPP8 and DPP9, thus exerting their effects through non-specific binding. This review highlights recent insights into the applicability of DPP inhibitors as novel pharmacological agents for inflammatory disease.

Introduction

The dipeptidyl peptidase (DPP)-4 family, also known as the S9b family, contains four structurally homologous enzymes, DPP4, fibroblast activation protein (FAP), DPP8 and DPP9 [1]. Enzymes within this family have a rare substrate specificity, cleaving N-terminal dipeptides from regulatory factors containing proline or alanine in the penultimate position [2]. The most extensively studied and well-characterized member of the DPP family is DPP4, a ubiquitously expressed transmembrane glycoprotein with known substrates that include several growth factors, neuropeptides and chemokines (Table 1). DPP4 is also known as the cell surface antigen CD26 and has a co-stimulatory function in the immune response [3]. There is increased awareness of the importance of the physiological functions of DPP8 and DPP9 [1]. DPP2, which belongs to the S28 serine protease family, lacks structural homology to members of the S9b family; however, it is able to bind some DPP inhibitors and has been reviewed in detail by Maes et al. [4].

DPP4 was initially identified as a therapeutic target for type 2 diabetes owing to its degradation of the incretin, glucagon-like peptide (GLP)-1. Since then, several pharmaceutical companies have released novel inhibitors, commonly referred to as the gliptins, that target the enzyme activity of DPP4, thus prolonging the insulinotrophic effects of GLP1 [5]. Altered DPP activity has been reported in a number of disease pathologies (Table 2). In vivo and in vitro studies have described the anti-inflammatory properties of non-selective DPP inhibitors, including val-pyrr, Ile-Thia Lys[Z(NO₂)]-thiazolidide and Lys[Z(NO₂)]-pyrrolidide, suggesting pharmacological application of this novel drug class for inflammatory disease. This review summarizes the application of DPP inhibitors to a range of disease settings, including the clinical success of DPP4 inhibitors for type 2 diabetes, as well as pre-clinical studies in animal models of arthritis, multiple sclerosis (MS) and inflammatory bowel disease (IBD). Recent insights into the selectivity of DPP inhibitors and potential off-target inhibition are discussed.