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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Astrocytes / drug effects
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Astrocytes / enzymology
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Azabicyclo Compounds / chemical synthesis*
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Azabicyclo Compounds / chemistry
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Azabicyclo Compounds / pharmacology
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Brain / blood supply
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Brain / cytology
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Bridged Bicyclo Compounds / chemical synthesis
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Bridged Bicyclo Compounds / chemistry
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Bridged Bicyclo Compounds / pharmacology
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Carbamates / chemical synthesis*
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Carbamates / chemistry
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Carbamates / pharmacology
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Catalytic Domain
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Cell Line, Tumor
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Cell Membrane Permeability
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Dipeptidyl-Peptidase IV Inhibitors
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Drug Design
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Endothelial Cells / drug effects
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Endothelial Cells / enzymology
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Fibroblasts / drug effects
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Fibroblasts / enzymology
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Humans
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Models, Molecular
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Molecular Mimicry
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Nitriles / chemical synthesis*
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Nitriles / chemistry
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Nitriles / pharmacology
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Peptides / chemistry*
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Prolyl Oligopeptidases
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Protein Binding
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacology
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Serine Endopeptidases / chemistry*
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Serine Endopeptidases / metabolism
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / chemistry
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Serine Proteinase Inhibitors / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
Substances
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1-aza-7-benzyloxycarbonylamino-8-oxo-4-thiabicyclo(3.3.0)octane-2-carbonitrile
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Azabicyclo Compounds
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Bridged Bicyclo Compounds
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Carbamates
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Dipeptidyl-Peptidase IV Inhibitors
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Nitriles
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Peptides
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Pyrrolidines
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Serine Proteinase Inhibitors
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Serine Endopeptidases
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PREPL protein, human
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Prolyl Oligopeptidases