Referencia

Santos J, Gracia P, Navarro S, Peña-Díaz S, Pujols J, Cremades N, Pallarès I, Ventura S. α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity. Nat Commun. 2021 Jun 18;12(1):3752. doi: 10.1038/s41467-021-24039-2. PMID: 34145261.Imagen portada NCOMS

Autores

Jaime Santos, Pablo Gracia, Susanna Navarro, Samuel Peña-Díaz, Jordi Pujols, Nunilo Cremades, Irantzu Pallarès, Salvador Ventura.

Resumen

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.

Descripción

En este estudio hemos identificado un péptido humano, LL-37, que se encuentra en el cerebro y es capaz de interaccionar con afinidad nanomolar con los agregados de α-sinucleína, los principales desencadenantes a nivel molecular de la enfermedad de Parkinson. Esta interacción bloquea la progresión amiloide y suprime su toxicidad asociada, teniendo una posible aplicación terapéutica. Este tipo de péptidos también constituyen una herramienta atractiva para el diagnostico, dado que discriminan entre especies funcionales y tóxicas de α-sinucleína. Este trabajo sugiere que este tipo de péptidos pueden ser un mecanismo natural protector de nuestro organismo.

Imagen grupo

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de Plegamiento de Proteínas y Enfermedades Conformacionales de la Universidad Autónoma de Barcelona combina el uso de análisis in silico y caracterizaciones biofísicas en el estudio de aspectos fundamentales de la bioquímica como son el plegamiento/mal plegamiento de las proteínas y la agregación proteica. Esta aproximación multidisciplinar les ha permitido profundizar en las bases moleculares de las enfermedades conformacionales, identificar y proponer nuevas aproximaciones terapéuticas y explotar la agregación amiloide para la generación de nuevos biomateriales.

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