Design and synthesis of statine-based cell-permeable peptidomimetic inhibitors of human beta-secretase.
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.
Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, California 94080, USA.
Roy K
RK
Hom
Larry Y
LY
Fang
Shumeye
S
Mamo
Jay S
JS
Tung
Ashley C
AC
Guinn
Don E
DE
Walker
David L
DL
Davis
Andrea F
AF
Gailunas
Eugene D
ED
Thorsett
Sukanto
S
Sinha
Jeroen E
JE
Knops
Nancy E
NE
Jewett
John P
JP
Anderson
Varghese
V
John
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000596:Amino Acids; D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human; C013165:statine