title: Characterization of cholyl-leu-val-phe-phe-ala-OH as an inhibitor of amyloid beta-peptide polymerization.
abstract: Cholyl-LVFFA-OH (1, PPI-368) is an organic-modified peptide based on the sequence of amyloid beta-peptide (A beta). It is a potent and selective inhibitor of A beta polymerization that blocks the formation of neurotoxic species of A beta. In a nucleation-dependent polymerization assay of 50 microM A beta(1-40), equimolar concentrations of PPI-368 block polymerization based on turbidity and electron microscopy. Monomeric A beta(1-40) and A beta(1-42) are non-toxic when incubated with neuronal cell lines, but become toxic during polymerization. PPI-368 coordinately delays the onset of polymerization and the formation of neurotoxic A beta species for both peptides. In a polymerization extension assay seeded with pre-formed A beta polymer, similar inhibition and dose-dependency phenomena are observed with PPI-368. Radiolabeled PPI-368 is incorporated into fibrils during polymerization demonstrating binding to A beta peptide within afibrillar structure. Gel-filtration studies show progressive disappearance of A beta monomer and concomitant appearance of soluble higher molecular weight oligomers. In the presence of submolar concentrations of PPI-368, monomeric A beta is still present and oligomers are not observed PPI-368 does not inhibit the polymerization of other amyloidogenic proteins such as transthyretin (TTR) or islet amyloid polypeptide (IAPP(20-29).
authors.affiliation: Praecis Pharmaceuticals Incorporated, Waltham, MA 02451-1420, USA. mark.findeis@praecis.com
authors.forename: M A
authors.initials: MA
authors.lastname: Findeis
authors.forename: J J
authors.initials: JJ
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Kelley
authors.forename: J D
authors.initials: JD
authors.lastname: Wakefield
authors.forename: M H
authors.initials: MH
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Chin
authors.forename: W
authors.initials: W
authors.lastname: Kubasek
authors.forename: S M
authors.initials: SM
authors.lastname: Molineaux
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity / Q000648:ultrastructure; D000818:Animals; D001704:Biopolymers / Q000737:chemistry / Q000633:toxicity; D002793:Cholic Acids / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008854:Microscopy, Electron; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D001704:Biopolymers; D002793:Cholic Acids; D009842:Oligopeptides; C462532:PPI 368