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

α-Synuclein aggregation is a key driver of neurodegeneration in Parkinson’s disease and related syndromes. Accordingly, obtaining a molecule that targets α-synuclein toxic assemblies with high affinity is a long-pursued objective. Here, we exploit the biophysical properties of toxic oligomers and am...

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Autores principales: Santos, Jaime, Gracia, Pablo, Navarro, Susanna, Peña-Díaz, Samuel, Pujols, Jordi, Cremades, Nunilo, Pallarès, Irantzu, Ventura, Salvador
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213730/
https://www.ncbi.nlm.nih.gov/pubmed/34145261
http://dx.doi.org/10.1038/s41467-021-24039-2
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author Santos, Jaime
Gracia, Pablo
Navarro, Susanna
Peña-Díaz, Samuel
Pujols, Jordi
Cremades, Nunilo
Pallarès, Irantzu
Ventura, Salvador
author_facet Santos, Jaime
Gracia, Pablo
Navarro, Susanna
Peña-Díaz, Samuel
Pujols, Jordi
Cremades, Nunilo
Pallarès, Irantzu
Ventura, Salvador
author_sort Santos, Jaime
collection PubMed
description α-Synuclein aggregation is a key driver of neurodegeneration in Parkinson’s disease and related syndromes. Accordingly, obtaining a molecule that targets α-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 α-helical peptides that bind to these α-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 α-synuclein species.
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spelling pubmed-82137302021-07-01 α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity Santos, Jaime Gracia, Pablo Navarro, Susanna Peña-Díaz, Samuel Pujols, Jordi Cremades, Nunilo Pallarès, Irantzu Ventura, Salvador Nat Commun Article α-Synuclein aggregation is a key driver of neurodegeneration in Parkinson’s disease and related syndromes. Accordingly, obtaining a molecule that targets α-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 α-helical peptides that bind to these α-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 α-synuclein species. Nature Publishing Group UK 2021-06-18 /pmc/articles/PMC8213730/ /pubmed/34145261 http://dx.doi.org/10.1038/s41467-021-24039-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Santos, Jaime
Gracia, Pablo
Navarro, Susanna
Peña-Díaz, Samuel
Pujols, Jordi
Cremades, Nunilo
Pallarès, Irantzu
Ventura, Salvador
α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity
title α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity
title_full α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity
title_fullStr α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity
title_full_unstemmed α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity
title_short α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity
title_sort α-helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213730/
https://www.ncbi.nlm.nih.gov/pubmed/34145261
http://dx.doi.org/10.1038/s41467-021-24039-2
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