Browsing by Subject "Proteomimetics"

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    β-Bracelets: Macrocyclic cross-β epitope mimics based on a tau conformational strain
    (American Chemical Society, 2023) Rajewski, Benjamin H.; Makwana, Kamlesh M.; Angera, Isaac J.; Geremia, Danielle K.; Zepeda, Anna R.; Hallinan, Grace I.; Vidal, Ruben; Ghetti, Bernardino; Serrano, Arnaldo L.; Del Valle, Juan R.; Pathology and Laboratory Medicine, School of Medicine
    The aggregation of misfolded tau into neurotoxic fibrils is linked to the progression of Alzheimer’s disease (AD) and related tauopathies. Disease-associated conformations of filamentous tau are characterized by hydrophobic interactions between sidechains on unique and distant β-strand modules within each protomer. Here, we report the design and diversity-oriented synthesis of β-arch peptide macrocycles comprised of the aggregation-prone PHF6 hexapeptide of tau and the cross-β module specific to the AD tau fold. Termed “β-bracelets”, these proteomimetics assemble in a sequence- and macrocycle-dependent fashion, resulting in amyloid-like fibrils that feature in-register parallel β-sheet structure. Backbone N-amination of a selected β-bracelet affords soluble inhibitors of tau aggregation. We further demonstrate that the N-aminated macrocycles block the prion-like cellular seeding activity of recombinant tau as well as mature fibrils from AD patient extracts. These studies establish β-bracelets as a new class of cross-β epitope mimic and demonstrate their utility in the rational design of molecules targeting amyloid propagation and seeding.