title: Chiral recognition in amyloid fiber growth.
abstract: Insoluble amyloid fibers represent a pathological signature of many human diseases. To treat such diseases, inhibition of amyloid formation has been proposed as a possible therapeutic strategy. d-Peptides, which possess high proteolytic stability and lessened immunogenicity, are attractive candidates in this context. However, a molecular understanding of chiral recognition phenomena for d-peptides and l-amyloids is currently incomplete. Here we report experiments on amyloid growth of individual enantiomers and their mixtures for two distinct polypeptide systems of different length and structural organization: a 44-residue covalently-linked dimer derived from a peptide corresponding to the [20-41]-fragment of human β2-microglobulin (β2m) and the 99-residue full-length protein. For the dimeric [20-41]β2m construct, a combination of electron paramagnetic resonance of nitroxide-labeled constructs and (13) C-isotope edited FT-IR spectroscopy of (13) C-labeled preparations was used to show that racemic mixtures precipitate as intact homochiral fibers, i.e. undergo spontaneous Pasteur-like resolution into a mixture of left- and right-handed amyloids. In the case of full-length β2m, the presence of the mirror-image d-protein affords morphologically distinct amyloids that are composed largely of enantiopure domains. Removal of the l-component from hybrid amyloids by proteolytic digestion results in their rapid transformation into characteristic long straight d-β2m amyloids. Furthermore, the full-length d-enantiomer of β2m was found to be an efficient inhibitor of l-β2m amyloid growth. This observation highlights the potential of longer d-polypeptides for future development into inhibitors of amyloid propagation. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.
authors.affiliation: Institut de Science et d'Ingénierie Supramoléculaires, International Center for Frontier Research in Chemistry, UMR 7006, Université de Strasbourg, 8 allée Gaspard Monge, 67000, Strasbourg, France.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Torbeev
authors.affiliation: Laboratory of Organic Chemistry, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, Zürich, CH-8093, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Grogg
authors.affiliation: Institut de Science et d'Ingénierie Supramoléculaires, International Center for Frontier Research in Chemistry, UMR 7006, Université de Strasbourg, 8 allée Gaspard Monge, 67000, Strasbourg, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Ruiz
authors.affiliation: Institut de Science et d'Ingénierie Supramoléculaires, International Center for Frontier Research in Chemistry, UMR 7006, Université de Strasbourg, 8 allée Gaspard Monge, 67000, Strasbourg, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Boehringer
authors.affiliation: Laboratoire de Bioélectrochimie et Spectroscopie, Chimie de la Matière Complexe, UMR 7140, Université de Strasbourg-CNRS, 1 rue Blaise Pascal, 67070, Strasbourg, France.
authors.forename: Alicia
authors.initials: A
authors.lastname: Schirer
authors.affiliation: Laboratoire de Bioélectrochimie et Spectroscopie, Chimie de la Matière Complexe, UMR 7140, Université de Strasbourg-CNRS, 1 rue Blaise Pascal, 67070, Strasbourg, France.
authors.forename: Petra
authors.initials: P
authors.lastname: Hellwig
authors.affiliation: Laboratory of Physical Chemistry, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, Zürich, CH-8093, Switzerland.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Jeschke
authors.affiliation: Laboratory of Organic Chemistry, ETH Zurich, Vladimir-Prelog-Weg 1-5/10, Zürich, CH-8093, Switzerland.
authors.forename: Donald
authors.initials: D
authors.lastname: Hilvert
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D013237:Stereoisomerism; D001613:beta 2-Microglobulin / Q000737:chemistry*
chemical_list: D000682:Amyloid; D010455:Peptides; D001613:beta 2-Microglobulin
keywords: chemical protein synthesis; mirror-image proteins; protein misfolding and aggregation; β2-microglobulin