Selection and Characterization of Tau Binding ᴅ-Enantiomeric Peptides with Potential for Therapy of Alzheimer Disease

• Published in: PloS one Vol. 11; no. 12; p. e0167432
• Main Authors: Dammers, Christina, Yolcu, Deniz, Kukuk, Laura, Willbold, Dieter, Pickhardt, Marcus, Mandelkow, Eckhard, Horn, Anselm H C, Sticht, Heinrich, Malhis, Marwa Nidal, Will, Nadja, Schuster, Judith, Funke, Susanne Aileen
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2016; Public Library of Science (PLoS)
• Subjects: Agglomeration; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amino Acid Sequence; Amino acids; Animal cognition; Binding; Binding Sites; Biocompatibility; Biology and Life Sciences; Brain research; Dementia; Diagnostic software; Diagnostic systems; Disease; Drug development; Dynamic Light Scattering; Fibrils; Fluoresceins - chemistry; Humans; Immunogenicity; Isoforms; Medicine and Health Sciences; Molecular Dynamics Simulation; Neurodegenerative diseases; Neurofibrillary tangles; Oligomers; Oligopeptides - chemistry; Oligopeptides - metabolism; Oligopeptides - therapeutic use; Pathology; Peptide Library; Peptides; Phage display; Phages; Protein Aggregates; Protein Binding; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Protein Structure, Secondary; Proteins; Recombinant Proteins - biosynthesis; Recombinant Proteins - chemistry; Recombinant Proteins - isolation & purification; Research and Analysis Methods; Self-assembly; Stereoisomerism; Tau protein; tau Proteins - chemistry; tau Proteins - genetics; tau Proteins - metabolism; Transgenic animals; Trends; United States > US; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0167432

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.