Survey of Dipeptidyl Peptidase III Inhibitors: From Small Molecules of Microbial or Synthetic Origin to Aprotinin

Abstract

Dipeptidyl peptidase III (DPP III) was originally thought to be a housekeeping enzyme that contributes to intracellular peptide catabolism. More specific roles for this cytosolic metallopeptidase, in the renin-angiotensin system and oxidative stress regulation, were confirmed, or recognized, only recently. To prove indicated (patho)physiological functions of DPP III in cancer progression, cataract formation and endogenous pain modulation, or to reveal new ones, selective and potent inhibitors are needed. This review encompasses natural and synthetic compounds with experimentally proven inhibitory activity toward mammalian DPP III. Except for the polypeptide aprotinin, all others are small molecules and include flavonoids, coumarin and benzimidazole derivatives. Presented are current strategies for the discovery or development of DPP III inhibitors, and mechanisms of inhibitory actions. The most potent inhibitors yet reported (propioxatin A and B, Tyr-Phe- and Phe-Phe-NHOH, and JMV-390) are active in low nanomolar range and contain hydroxamic acid moiety. High inhibitory potential possesses oligopeptides from the hemorphin group, valorphin and tynorphin, which are poor substrates of DPP III. The crystal structure of human DPP III-tynorphin complex enabled the design of the transition-state peptidomimetics inhibitors, effective in low micromolar concentrations. A new direction in the field is the development of fluorescent inhibitor for monitoring DPP III activity.

Distinctive Formation of a DNA–Protein Cross-Link during the Repair of DNA Oxidative Damage: Insights into Human Disease from MD Simulations and QM/MM Calculations

“…However, this is just one example among over 80 MUTYH missense and truncating variants whose functions are unclear. , There is also evidence that designing novel pharmaceuticals to target enzymes involved in DNA repair pathways may afford successful cancer treatments by increasing the efficacy of anticancer drugs or targeting DNA-repair defective cancers, − and highly specific and potent small molecule inhibitors have already been designed for enzymes that share mechanistic features with DNA glycosylases like MUTYH. − However, to aid the prediction of the dysfunction of MAP-related MUTYH variants in humans and develop possible cancer treatment strategies, the atomic level details of the chemistry facilitated by MUTYH are required. Indeed, structural information has proven essential for the rational development of small-molecule (transition state analogue) inhibitors. − …”

Plant-Derived Proteins and Peptides as Potential Immunomodulators

“…Dipeptidyl peptidase-III (DPP-III; EC 3.4.14.4) is a proteolytic enzyme which catalyzes hydrolytic cleavage of dipeptides from peptide substrates (from the N-terminal side). It was isolated from extracts of the bovine pituitary gland and showed relatively high specificity against a series of peptides, i.e., from tetrapeptides to oktapeptides [ 111 ]. DPP-III exhibits a high affinity to bioactive peptides, anigotensins (angiotensin-2, angiotensin-3), enkephalins, and endomorphins.…”

“…DPP-III exhibits a high affinity to bioactive peptides, anigotensins (angiotensin-2, angiotensin-3), enkephalins, and endomorphins. It hydrolyzes pentapeptides and Leu- and Met-enkephalin at the Gly2–Gly3 bond as the so-called enkephalinase B [ 80 , 111 ]. Leu-enkephalin is an important brain neurotransmitter that interacts with morphine receptors and reduces pain.…”

“…The increased concentration of DPP-III was observed in endometrial and ovarian malignancies, whereas its overexpression was correlated with a poor prognosis for human breast cancer and colorectal cancer patients. In turn, the elevated concentration of this enzyme was determined in the plasma of patients with sepsis [ 111 ].…”

DPP3: From biomarker to therapeutic target of cardiovascular diseases

“…Ang II forms a cis-peptide in a wheel-like conformation between histidine-6 and proline-7 during hydrolysis ( 99 ), meanwhile the binding site of DPP3 can bend to fully accommodate upon binding to Ang II and catalytic substrate. It was found that purified angiotensin-(1–7) [Ang-(1–7)] peptidase and DPP3 exhibited the same Ang-(1–7) hydrolysis profile, and both enzymatic activities were inhibited by the metallopeptidase inhibitor JMV-390 ( 100 ). DPP3 can sequentially hydrolyze Ang-(1–7) to Ang-(3–7) and rapidly convert Ang-(3–7) to Ang-(5–7) ( 101 ).…”