doi:10.1038/s41467-021-24039-2engSantos, J.Gracia, P.Navarro, S.Peña-Díaz, S.Pujols, J.Cremades, N.Pallarès, I.Ventura, S.a-Helical peptidic scaffolds to target a-synuclein toxic species with nanomolar affinityART-2021-126796a-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).2021http://zaguan.unizar.es/record/11068310.1038/s41467-021-24039-2http://zaguan.unizar.es/record/110683oai:zaguan.unizar.es:110683info:eu-repo/grantAgreement/ES/MCIU-FEDER/PGC2018-096335-B-100info:eu-repo/grantAgreement/ES/MINECO-FEDER/BFU2015-64119-Pinfo:eu-repo/grantAgreement/ES/MINECO/RYC-2012-12068Nature communications 12, 1 (2021), 3752 [14 pp]byhttp://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccess