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

Jaime Santos, Pablo Gracia, Susanna Navarro, Samuel Peña-Díaz, Jordi Pujols, Nunilo Cremades (), Irantzu Pallarès () and Salvador Ventura ()
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Jaime Santos: Universitat Autònoma de Barcelona
Pablo Gracia: University of Zaragoza
Susanna Navarro: Universitat Autònoma de Barcelona
Samuel Peña-Díaz: Universitat Autònoma de Barcelona
Jordi Pujols: Universitat Autònoma de Barcelona
Nunilo Cremades: University of Zaragoza
Irantzu Pallarès: Universitat Autònoma de Barcelona
Salvador Ventura: Universitat Autònoma de Barcelona

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24039-2

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DOI: 10.1038/s41467-021-24039-2

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