Abstract
(Hydroxyethyl)urea peptidomimetics systematically altered at positions P2-P3' with hydrophobic D-amino acids were synthesized. An all D-amino acid containing analogue was identified that effectively blocked gamma-secretase activity in a cell-free system (IC50 = 30 nM). Systematic alteration of the stereocenters of a potent compound revealed interdependence between the various positions. Although typically less potent than their L-peptidomimetic counterparts, selected all D-amino acid containing analogues were equipotent to their counterparts in a cell-based assay when incubated for extended times.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acids / chemical synthesis*
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Amino Acids / chemistry
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Amino Acids / pharmacology
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Amyloid Precursor Protein Secretases
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Amyloid beta-Protein Precursor / biosynthesis
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Amyloid beta-Protein Precursor / genetics
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Animals
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Aspartic Acid Endopeptidases
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CHO Cells
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Cell-Free System
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Cricetinae
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Cricetulus
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Endopeptidases / chemistry
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Endopeptidases / metabolism*
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HeLa Cells
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Humans
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Molecular Mimicry
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Peptides / chemistry*
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Transfection
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Urea / analogs & derivatives*
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Urea / chemical synthesis*
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Urea / chemistry
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Urea / pharmacology
Substances
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Amino Acids
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Amyloid beta-Protein Precursor
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Peptides
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Protease Inhibitors
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Urea
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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BACE1 protein, human