a-Helical peptidic scaffolds to target a-synuclein toxic species with nanomolar affinity

Santos, J. ; Gracia, P. (Universidad de Zaragoza) ; Navarro, S. ; Peña-Díaz, S. ; Pujols, J. ; Cremades, N. (Universidad de Zaragoza) ; Pallarès, I. ; Ventura, S.

Resumen: a-Synuclein aggregation is a key driver of neurodegeneration in Parkinson’s disease and related syndromes. Accordingly, obtaining a molecule that targets a-synuclein toxic assemblies with high affinity is a long-pursued objective. Here, we exploit the biophysical properties of toxic oligomers and amyloid fibrils to identify a family of a-helical peptides that bind to these a-synuclein species with low nanomolar affinity, without interfering with the monomeric functional protein. This activity is translated into a high anti-aggregation potency and the ability to abrogate oligomer-induced cell damage. Using a structure-guided search we identify a human peptide expressed in the brain and the gastrointestinal tract with analogous binding, anti-aggregation, and detoxifying properties. The chemical entities we describe here may represent a therapeutic avenue for the synucleinopathies and are promising tools to assist diagnosis by discriminating between native and toxic a-synuclein species. © 2021, The Author(s).

Idioma: Inglés

DOI: 10.1038/s41467-021-24039-2

Año: 2021

Publicado en: Nature communications 12, 1 (2021), 3752 [14 pp]
ISSN: 2041-1723

Factor impacto JCR: 17.694 (2021)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 6 / 74 = 0.081 (2021) - Q1 - T1

Factor impacto CITESCORE: 23.2 - Biochemistry, Genetics and Molecular Biology (Q1) - Physics and Astronomy (Q1)

Factor impacto SCIMAGO: 4.846 - Chemistry (miscellaneous) (Q1) - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/ES/MCIU-FEDER/PGC2018-096335-B-100
Financiación: info:eu-repo/grantAgreement/ES/MINECO-FEDER/BFU2015-64119-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/RYC-2012-12068

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)