title: Compounds that bind APP and inhibit Abeta processing in vitro suggest a novel approach to Alzheimer disease therapeutics.
abstract: Extracellular deposits of aggregated amyloid-beta (Abeta) peptides are a hallmark of Alzheimer disease; thus, inhibition of Abeta production and/or aggregation is an appealing strategy to thwart the onset and progression of this disease. The release of Abeta requires processing of the amyloid precursor protein (APP) by both beta- and gamma-secretase. Using an assay that incorporates full-length recombinant APP as a substrate for beta-secretase (BACE), we have identified a series of compounds that inhibit APP processing, but do not affect the cleavage of peptide substrates by BACE1. These molecules also inhibit the processing of APP and Abeta by BACE2 and selectively inhibit the production of Abeta(42) species by gamma-secretase in assays using CTF99. The compounds bind directly to APP, likely within the Abeta domain, and therefore, unlike previously described inhibitors of the secretase enzymes, their mechanism of action is mediated through APP. These studies demonstrate that APP binding agents can affect its processing through multiple pathways, providing proof of concept for novel strategies aimed at selectively modulating Abeta production.
authors.affiliation: Biological Chemistry, Medicinal Chemistry, and Automated Biotechnology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Espeseth
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.forename: Craig A
authors.initials: CA
authors.lastname: Coburn
authors.forename: Kristen L G
authors.initials: KL
authors.lastname: Jones
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.forename: Paul D
authors.initials: PD
authors.lastname: Zuck
authors.forename: Berta
authors.initials: B
authors.lastname: Strulovici
authors.forename: Eric A
authors.initials: EA
authors.lastname: Price
authors.forename: Guoxin
authors.initials: G
authors.lastname: Wu
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Wolfe
authors.forename: Janet E
authors.initials: JE
authors.lastname: Lineberger
authors.forename: Mohinder
authors.initials: M
authors.lastname: Sardana
authors.forename: Katherine
authors.initials: K
authors.lastname: Tugusheva
authors.forename: Beth L
authors.initials: BL
authors.lastname: Pietrak
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Crouthamel
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Elizabeth Chen
authors.initials: EC
authors.lastname: Dodson
authors.forename: Renzo
authors.initials: R
authors.lastname: Bazzo
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Shi
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Yueming
authors.initials: Y
authors.lastname: Li
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases; D006367:HeLa Cells; D006801:Humans; D011480:Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human