This is a family of serine proteases that share the capacity to cleave Xaa-Pro dipeptides from N-termini of their substrates.
DPP4 is a validated drug target with >10 approved DPP4 inhibitors in clinical use for the treatment of type 2 diabetes mellitus, including the orally active drug vildagliptin. DPP8 and DPP9 have been shown participate in multiple biological processes and diseases, including tumour development, immune regulation, the inflammatory response and immune cell pyroptosis, energy metabolism, cell proliferation and apoptosis, cell adhesion and migration, and COVID-19 [4,11-12]. The delevopment of selective DPP8 or DPP9 inhibitors is underway to help differentiate the specific roles of each enzyme in physiological and/or pathological processes [2-3,9-10].

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2. Benramdane S, De Loose J, Beyens O, Van Rymenant Y, Vliegen G, Augustyns K, De Winter H, De Meester I, Van der Veken P. (2022) Vildagliptin-Derived Dipeptidyl Peptidase 9 (DPP9) Inhibitors: Identification of a DPP8/9-Specific Lead. ChemMedChem, 17 (15): e202200097. [PMID:35760756]

3. Benramdane S, De Loose J, Filippi N, Espadinha M, Beyens O, Rymenant YV, Dirkx L, Bozdag M, Feijens PB, Augustyns K et al.. (2023) Highly Selective Inhibitors of Dipeptidyl Peptidase 9 (DPP9) Derived from the Clinically Used DPP4-Inhibitor Vildagliptin. J Med Chem, 66 (18): 12717-12738. [PMID:37721854]

4. Cui C, Tian X, Wei L, Wang Y, Wang K, Fu R. (2022) New insights into the role of dipeptidyl peptidase 8 and dipeptidyl peptidase 9 and their inhibitors. Front Pharmacol, 13: 1002871. [PMID:36172198]

5. Davis JA, Singh S, Sethi S, Roy S, Mittra S, Rayasam G, Bansal V, Sattigeri J, Ray A. (2010) Nature of action of Sitagliptin, the dipeptidyl peptidase-IV inhibitor in diabetic animals. Indian J Pharmacol, 42 (4): 229-33. [PMID:20927248]

6. Eckhardt M, Langkopf E, Mark M, Tadayyon M, Thomas L, Nar H, Pfrengle W, Guth B, Lotz R, Sieger P et al.. (2007) 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J Med Chem, 50 (26): 6450-3. [PMID:18052023]

7. Gupta R, Walunj SS, Tokala RK, Parsa KV, Singh SK, Pal M. (2009) Emerging drug candidates of dipeptidyl peptidase IV (DPP IV) inhibitor class for the treatment of Type 2 Diabetes. Curr Drug Targets, 10 (1): 71-87. [PMID:19149538]

8. Jain MR, Joharapurkar AA, Kshirsagar SG, Patel VJ, Bahekar RH, Patel HV, Jadav PA, Patel PR, Desai RC. (2017) ZY15557, a novel, long acting inhibitor of dipeptidyl peptidase-4, for the treatment of Type 2 diabetes mellitus. Br J Pharmacol, 174 (14): 2346-2357. [PMID:28452143]

9. Jiménez VA. (2023) DPP9 Comes of Age: Highly Selective Inhibitors Promise New Therapeutic Opportunities. J Med Chem, 66 (18): 12715-12716. [PMID:37721863]

10. Kikuchi S, Wada A, Kamihara Y, Okazaki K, Jawaid P, Rehman MU, Kobayashi E, Susukida T, Minemura T, Nabe Y et al.. (2023) DPP8 Selective Inhibitor Tominostat as a Novel and Broad-Spectrum Anticancer Agent against Hematological Malignancies. Cells, 12 (7). [PMID:37048172]

11. Moore KP, Schwaid AG, Tudor M, Park S, Beshore DC, Converso A, Shipe WD, Anand R, Lan P, Moningka R et al.. (2022) A Phenotypic Screen Identifies Potent DPP9 Inhibitors Capable of Killing HIV-1 Infected Cells. ACS Chem Biol, 17 (9): 2595-2604. [PMID:36044633]

12. Sharif-Zak M, Abbasi-Jorjandi M, Asadikaram G, Ghoreshi ZA, Rezazadeh-Jabalbarzi M, Afsharipur A, Rashidinejad H, Khajepour F, Jafarzadeh A, Arefinia N et al.. (2022) CCR2 and DPP9 expression in the peripheral blood of COVID-19 patients: Influences of the disease severity and gender. Immunobiology, 227 (2): 152184. [PMID:35131543]

13. Zhang H, Maqsudi S, Rainczuk A, Duffield N, Lawrence J, Keane FM, Justa-Schuch D, Geiss-Friedlander R, Gorrell MD, Stephens AN. (2015) Identification of novel dipeptidyl peptidase 9 substrates by two-dimensional differential in-gel electrophoresis. FEBS J, 282 (19): 3737-57. [PMID:26175140]