The multifunctional regulatory post-proline protease dipeptidyl peptidase 9 and its inhibitors: new opportunities for therapeutics.

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.