Dipeptidyl Peptidase-4 (CD26): Knowing the Function before Inhibiting the Enzyme
Pp. 80-102 (23)
Elena Matteucci and Ottavio Giampietro
Dipeptidyl peptidase-4 (DPP4) or adenosine deaminase complexing protein 2
(ADCP 2) or T-cell activation antigen CD26 (EC 18.104.22.168.) 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.
CD26, dipeptidyl peptidase-4, DPP4 inhibitors, serine peptidase, type
2 diabetes mellitus.
Dipartimento di Medicina Clinica e Sperimentale, Via Roma 67, 56126 Pisa, Italy.