New insights into the role of dipeptidyl peptidase 8 and dipeptidyl peptidase 9 and their inhibitors

Abstract

Dipeptidyl peptidase 8 (DPP8) and 9 (DPP9) are widely expressed in mammals including humans, mainly locate in the cytoplasm. The DPP8 and DPP9 (DPP8/9) belong to serine proteolytic enzymes, they can recognize and cleave N-terminal dipeptides of specific substrates if proline is at the penultimate position. Because the localization of DPP8/9 is different from that of DPP4 and the substrates for DPP8/9 are not yet completely clear, their physiological and pathological roles are still being further explored. In this article, we will review the recent research advances focusing on the expression, regulation, and functions of DPP8/9 in physiology and pathology status. Emerging research results have shown that DPP8/9 is involved in various biological processes such as cell behavior, energy metabolism, and immune regulation, which plays an essential role in maintaining normal development and physiological functions of the body. DPP8/9 is also involved in pathological processes such as tumorigenesis, inflammation, and organ fibrosis. In recent years, related research on immune cell pyroptosis has made DPP8/9 a new potential target for the treatment of hematological diseases. In addition, DPP8/9 inhibitors also have great potential in the treatment of tumors and chronic kidney disease.

DPP3 expression promotes cell proliferation and migration in vitro and tumour growth in vivo, which is associated with poor prognosis of oesophageal carcinoma

“…Therefore, considering the present study, the effect of apoptosis may be most important after DPP reduction. Nevertheless, certain studies have reported that DPP8/9 inhibitors can induce pyroptosis in cell experiments (23)(24)(25). Ferroptosis can be inhibited by blocking DPP4 activity (26).…”

DPP8 Selective Inhibitor Tominostat as a Novel and Broad-Spectrum Anticancer Agent against Hematological Malignancies

“…A potential explanation for this duality is that 1G244 inhibits DPP8 and DPP9 by different mechanisms. Indeed, it has been suggested that 1G244’s inhibition of DPP8 is based on binding that is slow and tight [ 21 ], i.e., irreversible [ 11 ], while its inhibition of DPP9 is competitive [ 21 ]. However, studies using experimental 3D models have not demonstrated clear differences between the molecular structures of 1G244-liganded DPP8 and 1G244-liganded DPP9 to support the suggested hypothesis [ 22 ].…”

“…DPP8 substrates include inflammatory protein-10 (IP10), interfering T-cell chemokines (ITAC), and chemokines stromal cell-derived factor (SDF-1) [ 10 ], while DPP9 cleaves C-X-C motif chemokine 10 (CXCL10/IP10), S100-A10, SET, nucleobindin-1 (NUCB1), and interleukin-1 receptor antagonist protein (IL-1RA) as substrates [ 8 ]. In addition, numerous studies have shown that DPP8/9 is involved in immune system regulation and inflammation by the cleavage of these substrates [ 11 ].…”

“…Alternatively, 1G244 is a specific inhibitor of DPP8 and DPP9 [ 11 ]. We have reported that 1G244 triggers caspase-3-activation-mediated apoptosis in multiple myeloma (MM) cell lines and primary MM samples, and that this effect may be dependent on DPP8 inhibition [ 16 ].…”

Facile Multicomponent Synthesis of Oxazolidinones from Primary Amines and Cesium (Hydrogen)Carbonate

“…Two emerging potential targets for the development of anticancer, anti-inflammatory, or even anti-Covid19 drugs are the intracellular dipeptidyl peptidases 8 (DPP8) and 9 (DPP9). [7] Both proteases share highly similar active site architectures, thereby turning the development of DPP8 versus DPP9 selective inhibitors into a challenge. [8] We recently reported a 4-oxo-βlactam compound (1) as a promising DPP8 and DPP9 inhibitor (Figure 1).…”