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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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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. |
format | Online Article Text |
id | pubmed-8213730 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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