Direct-to-biology approach for the selective identification of ligands for alpha-synuclein aggregates
Year: 2026
Type: preprint
Abstract: The selective targeting of α-synuclein (α-syn) aggregates represents a critical challenge for the diagnosis and treatment of Parkinson’s disease and related synucleinopathies. While several ligands have been developed for amyloid imaging, most of them lack sufficient specificity for α-syn over other amyloid fibrils. We report here a direct-to-biology (D2B) strategy to accelerate the identification of such selective ligands. A library of 384 piperazine-derived compounds was synthesized in a plate-based format and screened to evaluate their affinity for α-syn pathogenic aggregates compared to amyloid-beta 42 (Aβ42) fibrils. Nine compounds were found to bind preferentially to α-syn aggregates, three of which displayed at least a four-fold increased binding compared to Aβ42. Further validation of those molecules using in vitro α-syn fibrils enabled to determine a new potent selective binder of fibrillar α-syn with moderate affinity (181 nM). These findings validate the potential of D2B approaches to accelerate specific ligand development for pathogenic protein aggregates.
Source: ChemRxiv
Institutions: Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Université Paris-Saclay, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Médicaments et Technologies pour la Santé, Centre National de la Recherche Scientifique, CEA Paris-Saclay - Etablissement de Fontenay-aux-roses, Molecular Imaging Research Center
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7211949283