title: Designed hairpin peptides interfere with amyloidogenesis pathways: fibril formation and cytotoxicity inhibition, interception of the preamyloid state.
abstract: Hairpin peptides bearing cross-strand Trp-Trp and Tyr-Tyr pairs at non-H-bonded strand sites modulate the aggregation of two unrelated amyloidogenic systems, human pancreatic amylin (hAM) and α-synuclein (α-syn), associated with type II diabetes and Parkinson's disease, respectively. In the case of hAM, we have previously reported that inhibition of amyloidogenesis is observed as an increase in the lag time to amyloid formation and a diminished thioflavin (ThT) fluorescence response. In this study, a reduced level of hAM fibril formation is confirmed by transmission electron microscopy imaging. Several of the hairpins tested were significantly more effective inhibitors than rat amylin. Moreover, a marked inhibitory effect on hAM-associated cytotoxicity by the more potent hairpin peptide is demonstrated. In the case of α-syn, the dominant effect of active hairpins was, besides a weakened ThT fluorescence response, the earlier appearance of insoluble aggregates that do not display amyloid characteristics with the few fibrils observed having abnormal morphology. We attribute the alteration of the α-synuclein aggregation pathway observed to the capture of a preamyloid state and diversion to nonamyloidogenic aggregates. These β-hairpins represent a new class of amyloid inhibitors that bear no sequence similarity to the amyloid-producing polypeptides that are inhibited. A mechanistic rationale for these effects is proposed.
authors.affiliation: Department of Chemistry, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Kelly N L
authors.initials: KN
authors.lastname: Huggins
authors.forename: Marco
authors.initials: M
authors.lastname: Bisaglia
authors.forename: Luigi
authors.initials: L
authors.lastname: Bubacco
authors.forename: Marianna
authors.initials: M
authors.lastname: Tatarek-Nossol
authors.forename: Aphrodite
authors.initials: A
authors.lastname: Kapurniotu
authors.forename: Niels H
authors.initials: NH
authors.lastname: Andersen
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000737:chemistry; D000818:Animals; D052160:Benzothiazoles; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000494:pharmacology / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D017510:Protein Folding; D055503:Protein Multimerization / Q000187:drug effects; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D058228:Islet Amyloid Polypeptide; D010455:Peptides; D011994:Recombinant Proteins; D013844:Thiazoles; D051844:alpha-Synuclein; C009462:thioflavin T