title: Constrained peptidomimetics reveal detailed geometric requirements of covalent prolyl oligopeptidase inhibitors.
abstract: Prolyl oligopeptidases cleave peptides on the carboxy side of internal proline residues and their inhibition has potential in the treatment of human brain disorders. Using our docking program fitted, we have designed a series of constrained covalent inhibitors, built from a series of bicyclic scaffolds, to study the optimal shape required for these small molecules. These structures bear nitrile functional groups that we predicted to covalently bind to the catalytic serine of the enzyme. Synthesis and biological assays using human brain-derived astrocytic cells and endothelial cells and human fibroblasts revealed that these compounds act as selective inhibitors of prolyl oligopeptidase activity compared to prolyl-dipeptidyl-aminopeptidase activity, are able to penetrate the cells and inhibit intracellular activities in intact living cells. This integrated computational and experimental study shed light on the binding mode of inhibitors in the enzyme active site and will guide the design of future drug-like molecules.
authors.affiliation: Department of Chemistry, McGill University, Montreal, Quebec, Canada H3A 2K6.
authors.forename: Janice
authors.initials: J
authors.lastname: Lawandi
authors.forename: Sylvestre
authors.initials: S
authors.lastname: Toumieux
authors.forename: Valentine
authors.initials: V
authors.lastname: Seyer
authors.forename: Philip
authors.initials: P
authors.lastname: Campbell
authors.forename: Sabine
authors.initials: S
authors.lastname: Thielges
authors.forename: Lucienne
authors.initials: L
authors.lastname: Juillerat-Jeanneret
authors.forename: Nicolas
authors.initials: N
authors.lastname: Moitessier
mesh_terms: D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000098:blood supply / Q000166:cytology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D054873:Dipeptidyl-Peptidase IV Inhibitors; D015195:Drug Design; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry*; D000085822:Prolyl Oligopeptidases; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C545539:1-aza-7-benzyloxycarbonylamino-8-oxo-4-thiabicyclo(3.3.0)octane-2-carbonitrile; D053961:Azabicyclo Compounds; D001643:Bridged Bicyclo Compounds; D002219:Carbamates; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D010455:Peptides; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases