Gialama, D., Vadukul, D.M., Thrush, R.J. et al. (2 more authors) (2024) A Potent Sybody Selectively Inhibits α-Synuclein Amyloid Formation by Binding to the P1 Region. Journal of Medicinal Chemistry, 67 (12). pp. 9857-9868. ISSN 0022-2623
Abstract
Increasing research efforts focus on exploiting antibodies to inhibit the amyloid formation of neurodegenerative proteins. Nevertheless, it is challenging to discover antibodies that inhibit this process in a specific manner. Using ribosome display, we screened for synthetic single-domain antibodies, i.e., sybodies, of the P1 region of α-synuclein (residues 36–42), a protein that forms amyloid in Parkinson’s disease and multiple-system atrophy. Hits were assessed for direct binding to a P1 peptide and the inhibition of amyloid formation. We discovered a sybody, named αSP1, that inhibits amyloid formation of α-synuclein at substoichiometric concentrations in a specific manner, even within highly crowded heterogeneous mixtures. Fluorescence resonance energy transfer-based binding assays and seeding experiments with and without αSP1 further demonstrate the importance of the P1 region for both primary and secondary nucleation mechanisms of amyloid assembly.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Authors. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Structural Molecular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 05 Jun 2024 10:42 |
Last Modified: | 07 Aug 2024 14:01 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acs.jmedchem.3c02408 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:213113 |