Prolyl specific peptidases​

​This small family of peptidases has been in the interest of UAMC and the research group of medical biochemistry (UA) since the 1980’s. Our group pioneered in the synthesis of potent and selective DPP IV inhibitors that were extensively used in transplantation and ischemia/reperfusion models, as well as in the characterisation of DPP IV substrates.26 This research formed the basis for the development of novel drugs for the treatment of type 2 diabetes by the pharmaceutical industry. Later on, our focus shifted to the development of inhibitors for the related enzymes DPP II, DPP8, DPP9, FAP and PREP. We developed the most potent, specific and orally bioavailable DPP II inhibitor.27 We also reported the first irreversible and reversible DPP8/9 inhibitors, and delivered PREP inhibitors that target an hitherto unexplored pocket of PREP.28, 29 More recently, we obtained a very potent FAP inhibitor with the highest specificity reported so far and excellent in vivo pharmacokinetic properties.30, 31 For this research, Pieter Van der Veken obtained the Galenusprijs (Prix Galien) for pharmacology. Ongoing work deals with the preparation and evaluation of activity-based probes and PET-imaging probes structurally derived from this FAP inhibitor and from the PREP-inhibitors mentioned earlier.


26. Belyaev, A.; Zhang, X. M.; Augustyns, K.; Lambeir, A. M.; De Meester, I.; Vedernikova, I.; Scharpe, S.; Haemers, A. Structure-activity relationship of diaryl phosphonate esters as potent irreversible dipeptidyl peptidase IV inhibitors. J. Med. Chem. 1999, 42, 1041-1052.27. Senten, K.; Van der Veken, P.; De Meester, I.; Lambeir, A. M.; Scharpe, S.; Haemers, A.; Augustyns, K. gamma-Amino-substituted analogues of 1- (S)-2,4-diaminobutanoyl piperidine as highly potent and selective dipeptidyl peptidase II inhibitors. J. Med. Chem. 2004, 47, 2906-2916.28. Van der Veken, P.; Soroka, A.; Brandt, I.; Chen, Y. S.; Maes, M. B.; Lambeir, A. M.; Chen, X.; Haemers, A.; Scharpe, S.; Augustyns, K.; De Meester, I. Irreversible inhibition of dipeptidyl peptidase 8 by dipeptide-derived diaryl phosphonates. J. Med. Chem. 2007, 50, 5568-5570.29. Van der Veken, P.; Fulop, V.; Rea, D.; Gerard, M.; Van Elzen, R.; Joossens, J.; Cheng, J. D.; Baekelandt, V.; De Meester, I.; Lambeir, A. M.; Augustyns, K. P2-Substituted N-Acylprolylpyrrolidine Inhibitors of Prolyl Oligopeptidase: Biochemical Evaluation, Binding Mode Determination, and Assessment in a Cellular Model of Synucleinopathy. J. Med. Chem. 2012, 55, 9856-9867.30. Jansen, K.; Heirbaut, L.; Cheng, J. D.; Joossens, J.; Ryabtsova, O.; Cos, P.; Maes, L.; Lambeir, A. M.; De Meester, I.; Augustyns, K.; Van der Veken, P. Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold. ACS Med. Chem. Lett. 2013, 4, 491-496.31. Jansen, K.; Heirbaut, L.; Verkerk, R.; Cheng, J. D.; Joossens, J.; Cos, P.; Maes, L.; Lambeir, A. M.; De Meester, I.; Augustyns, K.; Van der Veken, P. Extended Structure Activity Relationship and Pharmacokinetic Investigation of (4-Quinolinoyl)glycy1-2-cyanopyrrolidine Inhibitors of Fibroblast Activation Protein (FAP). J. Med. Chem. 2014, 57, 3053-3074.


​As a side project of the uPA inhibitors, we recently reported the first potent and selective KLK4 inhibitors.32


32. van Soom, J.; Crucitti, G. C.; Gladysz, R.; van der Veken, P.; Di Santo, R.; Stuyver, I.; Buck, V.; Lambeir, A. M.; Magdolen, V.; Joossens, J.; Augustyns, K. The first potent diphenyl phosphonate KLK4 inhibitors with unexpected binding kinetics. MedChemComm 2015, 6, 1954-1958.