N‑Amination Converts Amyloidogenic Tau Peptides into Soluble Antagonists of Cellular Seeding

• Published in: ACS chemical neuroscience Vol. 12; no. 20; pp. 3928 - 3938
• Main Authors: Makwana, Kamlesh M, Sarnowski, Matthew P, Miao, Jiayuan, Lin, Yu-Shan, Del Valle, Juan R
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 20.10.2021
• Subjects: Alzheimer Disease; Amination; Humans; Neurofibrillary Tangles - metabolism; Peptides; Protein Conformation, beta-Strand; tau Proteins - metabolism; tau; aggregation; amyloid; peptidomimetic; β-strand; PHF6
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.1c00528

The spread of neurofibrillary tangles composed of tau protein aggregates is a hallmark of Alzheimer’s and related neurodegenerative diseases. Early oligomerization of tau involves conformational reorganization into parallel β-sheet structures and supramolecular assembly into toxic fibrils. Despite the need for selective inhibitors of tau propagation, β-rich protein assemblies are inherently difficult to target with small molecules. Here, we describe a minimalist approach to mimic the aggregation-prone modules within tau. We carried out a backbone residue scan and show that amide N-amination completely abolishes the tendency of these peptides to self-aggregate, rendering them soluble mimics of ordered β-strands from the tau R2 and R3 domains. Several N-amino peptides (NAPs) inhibit tau fibril formation in vitro. We further demonstrate that NAPs 12 and 13 are effective at blocking the cellular seeding of endogenous tau by interacting with monomeric or fibrillar forms of extracellular tau. Peptidomimetic 12 is serum stable, non-toxic to neuronal cells, and selectivity inhibits the fibrilization of tau over Aβ42. Structural analysis of our lead NAPs shows considerable conformational constraint imposed by the N-amino groups. The described backbone N-amination approach provides a rational basis for the mimicry of other aggregation-prone peptides that drive pathogenic protein assembly.