ß-Bracelets: Macrocyclic Cross-ß Epitope Mimics Based on a Tau Conformational Strain.
J Am Chem Soc
; 145(42): 23131-23142, 2023 10 25.
Article
en En
| MEDLINE
| ID: mdl-37844142
ABSTRACT
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 side chains on unique and distant ß-strand modules within each protomer. Here, we report the design and diversity-oriented synthesis of ß-arch peptide macrocycles composed of the aggregation-prone PHF6 hexapeptide of tau and the cross-ß module specific to the AD tau fold. Termed "ß-bracelets", these proteomimetics assemble in a sequence- and macrocycle-dependent fashion, resulting in amyloid-like fibrils that feature in-register parallel ß-sheet structure. Backbone N-amination of a selected ß-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 ß-bracelets as a new class of cross-ß epitope mimics and demonstrate their utility in the rational design of molecules targeting amyloid propagation and seeding.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Priones
/
Tauopatías
/
Enfermedad de Alzheimer
Límite:
Humans
Idioma:
En
Revista:
J Am Chem Soc
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos