The prolyl-aminodipeptidases and their inhibitors as therapeutic targets for fibrogenic disorders.
Many biologically active peptides are protected from general proteolytic degradation by evolutionary conserved prolines (Pro), due to conformational constraints imposed by the Pro residue. Thus the biological importance of prolyl-specific peptidases points to a high potential for drug discovery for this family of enzymes. Panels of inhibitors have been synthesized and their effects, determined in biological models, suggest the inhibition of families of enzymes with similar activities. Prolyl-specific aminodipeptidases include dipeptidyl-aminodipeptidase IV (DPP IV)/CD26, DPP8, DPP9 and fibroblast activation protease-alpha (FAP-alpha)/seprase, able to release X-Pro dipeptides from the N-terminus of peptides. DPP IV inhibitors are in clinical use for type 2 diabetes. In this review, the expression and the potential functions of prolyl-aminodipeptidases are reviewed in diseases, and the inhibitors developed for these enzymes are discussed, with a specific focus on inhibitors able to discriminate between DPP IV and fibroblast activation protease-alpha (FAPalpha)/seprase as potential leads for the treatment of fibrogenic diseases.
Juillerat-Jeanneret
Lucienne
L
University Institute of Pathology, Bugnon 25, CH-1011 Lausanne, Switzerland. lucienne.juillerat@chuv.ch
Gerber-Lemaire
Sandrine
S
D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005355:Fibrosis / Q000188:drug therapy*; D018093:Gelatinases; D006801:Humans; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha
D000626:Aminopeptidases; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010450:Endopeptidases; D004791:Enzyme Inhibitors; D018093:Gelatinases; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C022450:prolyl aminopeptidase