Prolyl-Specific Peptidases and Their Inhibitors in Biological Processes

Lucienne      Juillerat-Jeanneret

doi:10.2174/2212796810802020097

Abstract

Proteases are major targets to treat human diseases. Many biologically active peptides are protected from general proteolytic degradation by evolutionary conserved prolines (Pro), due to conformational constraints imposed by the Pro residue, pointing to the biological importance and a high potential for drug discovery of prolyl-specific peptidases. Of the known human proteases only a few Pro-specific proteases have been described which include exopeptidases and endopeptidases. Dipeptidylpeptidase IV (DPP IV)/CD26, DPP8, DPP9 and fibroblast activation protein-α (FAP-α)/seprase are able to release X-Pro dipeptides from the N-terminus of peptides. DPP8 and FAP-α are also capable of prolyl-specific endoproteolytic activity. Prolyl oligopeptidase (POP) is a post-prolyl-cleaving endopeptidase. Several families of inhibitors have been synthesized and evaluated on purified enzymes and their effects determined in a few biological models, suggesting the inhibition of families of enzymes with similar activities. DPP IV inhibitors are under clinical evaluation for type 2 diabetes. Inhibitors of POP-like activities ameliorate cognitive functions in animal models and may be protective and/or therapeutic in neurodegenerative disorders. In this review, the expression of prolyl-specific enzymes in mammalians is reviewed, their potential functions and their enzymatic and biological characteristics, as well as the inhibitors developed for these enzymes, are discussed.

Keywords: Dipeptidyl peptidase, prolyl oligopeptidase, prolyl-specific proteases, seprase, fibroblast activation protein, inhibitors, diabetes, inflammation, cancer, neurodegeneration