A novel approach to identifying beta-secretase inhibitors: bis-statine peptide mimetics discovered using structure and spot synthesis.
Beta-secretase 1 (BACE1) is an aspartic protease believed to play a critical role in Alzheimer's disease. Inhibitors of this enzyme have been designed by incorporating the non-cleavable hydroxyethylene and statine isosteres into peptides corresponding to BACE1 substrate sequences. We sought to develop new methods to quickly characterize and optimize inhibitors based on the statine core. Minimal sequence requirements for binding were first established using both crystallography and peptide spot synthesis. These shortened peptide inhibitors were then optimized by using spot synthesis to perform iterative cycles of substitution and deletion. The present study resulted in the identification of novel "bis-statine" inhibitors shown by crystallography to have a unique binding mode. Our results demonstrate the application of peptide spot synthesis as an effective method for enhancing peptidomimetic drug discovery.
Department of Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.
Kristie Grove
KG
Bridges
Rajiv
R
Chopra
Laura
L
Lin
Kristine
K
Svenson
Amy
A
Tam
Guixian
G
Jin
Rebecca
R
Cowling
Frank
F
Lovering
Tatos N
TN
Akopian
Elizabeth
E
DiBlasio-Smith
Bethany
B
Annis-Freeman
Tod H
TH
Marvell
Edward R
ER
LaVallie
Richard S
RS
Zollner
Jonathan
J
Bard
William S
WS
Somers
Mark L
ML
Stahl
Ronald W
RW
Kriz
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D001671:Biochemistry / Q000379:methods*; D019921:Biotinylation; D016466:CHO Cells; D006224:Cricetinae; D003460:Crystallization; D003461:Crystallography; D010450:Endopeptidases / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011487:Protein Conformation
D000596:Amino Acids; D010455:Peptides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; C013165:statine