title: Structure-based design and synthesis of macrocyclic peptidomimetic beta-secretase (BACE-1) inhibitors.
abstract: The hydroxyethylene octapeptide inhibitor OM99-2 served as starting point to create the tripeptide inhibitor 1 and its analogues 2a and b. An X-ray co-crystal structure of 1 with BACE-1 allowed the design and syntheses of a series of macrocyclic analogues 3a-h covalently linking the P1 and P3 side-chains. These inhibitors show improved enzymatic potency over their open-chain analogue. Inhibitor 3h also shows activity in a cellular system.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, PO Box, CH-4002 Basel, Switzerland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Machauer
authors.forename: Siem
authors.initials: S
authors.lastname: Veenstra
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rondeau
authors.forename: Marina
authors.initials: M
authors.lastname: Tintelnot-Blomley
authors.forename: Claudia
authors.initials: C
authors.lastname: Betschart
authors.forename: Ulf
authors.initials: U
authors.lastname: Neumann
authors.forename: Paolo
authors.initials: P
authors.lastname: Paganetti
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D047028:Macrocyclic Compounds; C414614:OM99-2; D009842:Oligopeptides; D010446:Peptide Fragments; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human