Nguyen Jasmine Minh Hang, Zolg Samuel, Geiss-Friedlander Ruth, Gorrell Mark Douglas
Centenary Institute, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia.
Center of Biochemistry and Molecular Cell Research, Albert-Ludwigs-Universität, 79104, Freiburg, Germany.
Cell Mol Life Sci. 2025 Apr 28;82(1):187. doi: 10.1007/s00018-025-05719-4.
Dipeptidyl Peptidase 9 (DPP9) is a prolyl amino dipeptidylpeptidase that can cut a post-proline peptide bond at the penultimate position at the N-terminus. By removing N-terminal prolines, this intracellular peptidase acts as an upstream regulator of the N-degron pathway. DPP9 has crucial roles in inflammatory regulation, DNA repair, cellular homeostasis, and cellular proliferation, while its deregulation is linked to cancer and immunological disorders. Currently, there is no fully selective chemical inhibitor and the DPP9 knockout transgenic mouse model is conditional. Mice and humans in which DPP9 catalytic activity is absent die neonatally. DPP9 inhibition for manipulating DPP9 activity in vivo has potential uses and there is rapid progress towards DPP9 selectivity, with 170x selectivity achieved. This review discusses roles of DPP9 in biology and diseases and potential applications of compounds that inhibit DPP9 and its related proteases.
二肽基肽酶9（DPP9）是一种脯氨酰氨基二肽基肽酶，可在N端倒数第二位切割脯氨酸后肽键。通过去除N端脯氨酸，这种细胞内肽酶作为N-降解途径的上游调节因子发挥作用。DPP9在炎症调节、DNA修复、细胞稳态和细胞增殖中起关键作用，而其失调与癌症和免疫紊乱有关。目前，尚无完全选择性的化学抑制剂，且DPP9基因敲除转基因小鼠模型是条件性的。缺乏DPP9催化活性的小鼠和人类在出生时死亡。抑制DPP9以在体内操纵其活性具有潜在用途，并且在提高DPP9选择性方面取得了快速进展，已实现170倍的选择性。本综述讨论了DPP9在生物学和疾病中的作用以及抑制DPP9及其相关蛋白酶的化合物的潜在应用。
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