State-selective inhibition of alpha-synuclein aggregation by de novo oligomer-binding proteins
- 1Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK
Abstract
The intrinsically disordered, non-amyloid-{beta} component domain of -synuclein (Syn) drives aggregation in Parkinson's disease but lacks a stable epitope for structure-based drug design. We used deep learning-based protein design to generate de novo binders capturing this region in a {beta}-strand conformation. Three designs bound Syn with nanomolar affinities, with solution NMR spectroscopy supporting the intended fold. All three suppressed fibril formation at substoichiometric ratios, and fitting of aggregation kinetics resolved the microscopic steps inhibited by each. Notably, one binder preferentially engaged oligomers and inhibited secondary nucleation, both closely linked to toxicity. In cells, all three suppressed seeded Syn assembly, with the oligomer binder being the most effective. Together, these findings establish a set of molecules that target distinct aggregation intermediates and mechanistically reshape Syn assembly.
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BibTeX
@misc{zhang2026stateselective,
title = {{State-selective inhibition of alpha-synuclein aggregation by de novo oligomer-binding proteins}},
author = {Y. Zhang and H. L. Han and L. Ortigosa-Pascual and U. Z. Miles and J. Wei and L. Berkowicz and F. Snow and D. Tu and G. Meisl and S. Sansaria and T. J. Nott and H. Laman and R. Halfmann and A. C. McShan and D. D. Sahtoe and T. P. J. Knowles},
howpublished = {bioRxiv},
year = {2026},
month = jul,
doi = {10.64898/2026.07.13.738012},
url = {https://www.biorxiv.org/content/10.64898/2026.07.13.738012v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - State-selective inhibition of alpha-synuclein aggregation by de novo oligomer-binding proteins
AU - Y. Zhang
AU - H. L. Han
AU - L. Ortigosa-Pascual
AU - U. Z. Miles
AU - J. Wei
AU - L. Berkowicz
AU - F. Snow
AU - D. Tu
AU - G. Meisl
AU - S. Sansaria
AU - T. J. Nott
AU - H. Laman
AU - R. Halfmann
AU - A. C. McShan
AU - D. D. Sahtoe
AU - T. P. J. Knowles
PY - 2026
DA - 2026/07/13
PB - bioRxiv
DO - 10.64898/2026.07.13.738012
UR - https://www.biorxiv.org/content/10.64898/2026.07.13.738012v2
AB - The intrinsically disordered, non-amyloid-{beta} component domain of -synuclein (Syn) drives aggregation in Parkinson's disease but lacks a stable epitope for structure-based drug design. We used deep learning-based protein design to generate de novo binders capturing this region in a {beta}-strand conformation. Three designs bound Syn with nanomolar affinities, with solution NMR spectroscopy supporting the intended fold. All three suppressed fibril formation at substoichiometric ratios, and fitting of aggregation kinetics resolved the microscopic steps inhibited by each. Notably, one binder preferentially engaged oligomers and inhibited secondary nucleation, both closely linked to toxicity. In cells, all three suppressed seeded Syn assembly, with the oligomer binder being the most effective. Together, these findings establish a set of molecules that target distinct aggregation intermediates and mechanistically reshape Syn assembly.
ER -