title: Structure-based design: potent inhibitors of human brain memapsin 2 (beta-secretase).
abstract: Memapsin 2 (beta-secretase) is one of two proteases that cleave the beta-amyloid precursor protein (APP) to produce the 40-42 residue amyloid-beta peptide (Abeta) in the human brain, a key event in the progression of Alzheimer's disease. On the basis of the X-ray crystal structure of our lead inhibitor (2, OM99-2 with eight residues) bound to memapsin, we have reduced the molecular weight and designed potent memapsin inhibitors. Structure-based design and preliminary structure-activity studies have been presented.
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, USA. arunghos@uic.edu
authors.forename: A K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: G
authors.initials: G
authors.lastname: Bilcer
authors.forename: C
authors.initials: C
authors.lastname: Harwood
authors.forename: R
authors.initials: R
authors.lastname: Kawahama
authors.forename: D
authors.initials: D
authors.lastname: Shin
authors.forename: K A
authors.initials: KA
authors.lastname: Hussain
authors.forename: L
authors.initials: L
authors.lastname: Hong
authors.forename: J A
authors.initials: JA
authors.lastname: Loy
authors.forename: C
authors.initials: C
authors.lastname: Nguyen
authors.forename: G
authors.initials: G
authors.lastname: Koelsch
authors.forename: J
authors.initials: J
authors.lastname: Ermolieff
authors.forename: J
authors.initials: J
authors.lastname: Tang
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D015195:Drug Design; D010450:Endopeptidases; D006801:Humans; D008958:Models, Molecular; D008970:Molecular Weight; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: C414614:OM99-2; D009842:Oligopeptides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human