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

JAIME SANTOS SUAREZ, Pablo Gracia, Susanna Navarro, Samuel Peña-Díaz, Jordi Pujols, Nunilo Cremades, Irantzu Pallarès, Salvador Ventura

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Article number3752
Pages (from-to)3752
Number of pages14
JournalNature communications
Volume12
Issue number1
DOIs
Publication statusPublished - 1 Dec 2021

Keywords

  • Amyloid/metabolism
  • Brain/metabolism
  • Gastrointestinal Tract/metabolism
  • Humans
  • Parkinson Disease/pathology
  • Protein Aggregation, Pathological/pathology
  • alpha-Synuclein/metabolism

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