title: Selection and Characterization of Tau Binding ᴅ-Enantiomeric Peptides with Potential for Therapy of Alzheimer Disease.
abstract: A variety of neurodegenerative disorders, including Alzheimer disease (AD), are associated with neurofibrillary tangles composed of the tau protein, as well as toxic tau oligomers. Inhibitors of pathological tau aggregation, interrupting tau self-assembly, might be useful for the development of therapeutics. Employing mirror image phage display with a large peptide library (over 109 different peptides), we have identified tau fibril binding peptides consisting of d-enantiomeric amino acids. d-enantiomeric peptides are extremely protease stable and not or less immunogenic than l-peptides, and the suitability of d-peptides for in vivo applications have already been demonstrated. Phage display selections were performed using fibrils of the d-enantiomeric hexapeptide VQIVYK, representing residues 306 to 311 of the tau protein, as a target. VQIVYK has been demonstrated to be important for fibril formation of the full lengths protein and forms fibrils by itself. Here, we report on d-enantiomeric peptides, which bind to VQIVYK, tau isoforms like tau3RD (K19) as well as to full lengths tau fibrils, and modulate the aggregation of the respective tau form. The peptides are able to penetrate cells and might be interesting for therapeutic and diagnostic applications in AD research.
authors.affiliation: Institute of Complex Systems (ICS-6), Forschungszentrum Jülich, Jülich, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Dammers
authors.affiliation: Institute of Complex Systems (ICS-6), Forschungszentrum Jülich, Jülich, Germany.
authors.forename: Deniz
authors.initials: D
authors.lastname: Yolcu
authors.affiliation: Institute of Complex Systems (ICS-6), Forschungszentrum Jülich, Jülich, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Kukuk
authors.affiliation: Institute of Complex Systems (ICS-6), Forschungszentrum Jülich, Jülich, Germany.|Institut für Physikalische Biologie, Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany.|CAESAR Research Center, Bonn, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Pickhardt
authors.affiliation: Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany.|CAESAR Research Center, Bonn, Germany.|Max Planck Institute for Metabolism Research, Köln, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.affiliation: Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Anselm H C
authors.initials: AH
authors.lastname: Horn
authors.affiliation: Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.affiliation: Bioanalytik, Hochschule für angewandte Wissenschaften, Coburg, Germany.
authors.forename: Marwa Nidal
authors.initials: MN
authors.lastname: Malhis
authors.affiliation: Bioanalytik, Hochschule für angewandte Wissenschaften, Coburg, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Will
authors.affiliation: Bioanalytik, Hochschule für angewandte Wissenschaften, Coburg, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Schuster
authors.affiliation: Bioanalytik, Hochschule für angewandte Wissenschaften, Coburg, Germany.
authors.forename: Susanne Aileen
authors.initials: SA
authors.lastname: Funke
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D001665:Binding Sites; D000067493:Dynamic Light Scattering; D005452:Fluoresceins / Q000737:chemistry; D006801:Humans; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D019151:Peptide Library; D066329:Protein Aggregates; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D013237:Stereoisomerism; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D005452:Fluoresceins; D009842:Oligopeptides; D019151:Peptide Library; D066329:Protein Aggregates; D020033:Protein Isoforms; D011994:Recombinant Proteins; D016875:tau Proteins; C024098:6-carboxyfluorescein