Direct-to-biology approach for the selective identification of ligands for alpha-synuclein aggregates
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.
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BibTeX
@misc{ossard2026directtobiology,
title = {{Direct-to-biology approach for the selective identification of ligands for alpha-synuclein aggregates}},
author = {Gaëtan Ossard and Clémentine Pescheteau and Timothée D’Anfray and David-Alexandre Buisson and Jean-Christophe Cintrat and Ronald Melki and Eugénie Romero},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008497/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008497/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Direct-to-biology approach for the selective identification of ligands for alpha-synuclein aggregates
AU - Gaëtan Ossard
AU - Clémentine Pescheteau
AU - Timothée D’Anfray
AU - David-Alexandre Buisson
AU - Jean-Christophe Cintrat
AU - Ronald Melki
AU - Eugénie Romero
PY - 2026
DA - 2026/09/08
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008497/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008497/v1
AB - 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.
ER -