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bioRxiv · 10.1101/2021.03.12.435074

α-Helical peptidic scaffolds to target α-synuclein pathogenic species with high affinity and selectivity.

Santos, J.·Gracia, P.·Navarro, S.·Pena-Diaz, S.·Pujols, J.·Cremades, N.·Pallares, I.·Ventura, S.
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Abstract

-Synuclein aggregation is a key driver of neurodegeneration in Parkinsons disease and related syndromes. Accordingly, obtaining a molecule that targets -synuclein pathogenic assemblies with high affinity and selectivity is a long-pursued objective. Here, we have exploited the biophysical properties of toxic oligomers and amyloid fibrils to identify a family of -helical peptides that bind selectively to these -synuclein species with low nanomolar affinity, without interfering with the monomeric functional protein. This activity is translated into an unprecedented anti-aggregation potency and the ability to abrogate the oligomers toxicity. With a structure-function relationship in hand, we identified a human peptide expressed in the brain and in the gastrointestinal tract with exceptional binding, antiaggregation, and detoxifying properties, which suggests it might play a protective role against synucleinopathies. The chemical entities we describe here represent a new therapeutic paradigm and are promising tools to assist diagnosis by selectively detecting -synuclein pathogenic species in biofluids.

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Santos, J., Gracia, P., Navarro, S., Pena-Diaz, S., Pujols, J., Cremades, N., Pallares, I., Ventura, S.. 2021-03-13. α-Helical peptidic scaffolds to target α-synuclein pathogenic species with high affinity and selectivity.. https://doi.org/10.1101/2021.03.12.435074

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