Abstract
We describe the development of statine-based peptidomimetic inhibitors of human beta-secretase (BACE). The conversion of the peptide inhibitor 1 into cell-permeable peptidomimetic inhibitors of BACE was achieved through an iterative strategy of conceptually subdividing 1 into three regions: an N-terminal portion, a central statine-containing core, and a C-terminus. Replacement of the amino acid residues of 1 with moieties with less peptidic character was done with retention of BACE enzyme inhibitory activity. This approach led to the identification of the cell-permeable BACE inhibitor 38 that demonstrated BACE-mechanism-selective inhibition of Abeta secretion in human embryonic kidney cells.
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-Peptides / antagonists & inhibitors
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Amyloid beta-Peptides / biosynthesis
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Aspartic Acid Endopeptidases / antagonists & inhibitors*
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Cell Line
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Endopeptidases
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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Molecular Mimicry
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Oligopeptides / chemistry*
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Structure-Activity Relationship
Substances
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Amino Acids
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Amyloid beta-Peptides
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Enzyme Inhibitors
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Oligopeptides
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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BACE2 protein, human
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BACE1 protein, human
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statine