Dipeptidyl Peptidase-4 (CD26): Knowing the Function before Inhibiting the Enzyme

Dipeptidyl peptidase-4 (DPP4) or adenosine deaminase complexing protein 2 (ADCP 2) or T-cell activation antigen CD26 (EC 3.4.14.5.) is a serine exopeptidase belonging to the S9B protein family that cleaves X-proline dipeptides from the N-terminus of polypeptides, such as chemokines, neuropeptides, and peptide hormones. The enzyme is a type II transmembrane glycoprotein, expressed on the surface of many cell types, whose physiological functions have begun to emerge in recent years. Protein dimerisation is required for catalytic activity and glycosylation of the enzyme could impact on its physiological functions. The dimeric glycoprotein ADCP has been found linked to adenosine deaminase (ADA) whose relationship with lymphocyte maturationdifferentiation is well established.

Since implicated in the regulation of the biological activity of hormones and chemokines, such as glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, DPP4 inhibition offered a new potential therapeutic approach for type 2 diabetes mellitus as monotherapy and adjunct therapy to other oral agents. The clinical use of orally active inhibitors of DPP4 has been initially associated with side effects that have been in part attributed to the inhibition of related serine proteases, such as DPP8 and DPP9. Moreover, CD26 has a key role in immune regulation as a T cell activation molecule and in immune-mediated disorder; all-cause infections were found increased after sitagliptin treatment. So far, systematic reviews and meta-analysis on the efficacy and safety in human type 2 diabetes of orally active DPP4 inhibitors were published, but some questions remain open. Long-term evaluation of the risk-benefit ratio in controlled trials is still required, possibly through the use of multiple risk-benefit approaches across different indications and treatment populations. The review summarises present knowledge in the field and suggests some potential directions of future research.

Keywords: CD26, dipeptidyl peptidase-4, DPP4 inhibitors, serine peptidase, type 2 diabetes mellitus.