title: Peptide-based, irreversible inhibitors of gamma-secretase activity.
abstract: The characterization of the enzymes responsible for amyloid beta-peptide (Abeta) production is considered to be a primary goal towards the development of future therapeutics for the treatment of Alzheimer's disease. Inhibitors of gamma-secretase activity were critical in demonstrating that the presenilins (PSs) likely comprised at least part of the active site of the gamma-secretase enzyme complex, with two highly conserved membrane aspartates presumably acting as catalytic residues. However, whether or not these aspartates are actually the catalytic residues of the enzyme complex or are merely essential for normal PS function and/or maturation is still unknown. In this paper, we report the development of reactive inhibitors of gamma-secretase activity that are functionally irreversible. Since such inhibitors have been shown to bind catalytic residues in other aspartyl proteases (e.g., HIV protease), they might be used to determine if the transmembrane aspartates of PSs are involved directly in substrate cleavage.
authors.affiliation: Mayo Clinic Jacksonville, Birdsall Medical Research Building, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors.forename: Siân C
authors.initials: SC
authors.lastname: Piper
authors.forename: Zareen
authors.initials: Z
authors.lastname: Amtul
authors.forename: Laura
authors.initials: L
authors.lastname: Galiñanes-Garcia
authors.forename: Victor G
authors.initials: VG
authors.lastname: Howard
authors.forename: Chewki
authors.initials: C
authors.lastname: Ziani-Cherif
authors.forename: Chris
authors.initials: C
authors.lastname: McLendon
authors.forename: Marjorie J
authors.initials: MJ
authors.lastname: Rochette
authors.forename: Abdul
authors.initials: A
authors.lastname: Fauq
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: M Paul
authors.initials: MP
authors.lastname: Murphy
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D051880:Receptors, Notch; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D008565:Membrane Proteins; D009842:Oligopeptides; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human