Mapping the binding site topology of amyloid protein aggregates using multivalent ligands.
Fagan, Steven G
Spillantini, Maria Grazia
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Sanna, E., Rodrigues, M., Fagan, S. G., Chisholm, T. S., Kulenkampff, K., Klenerman, D., Spillantini, M. G., et al. (2021). Mapping the binding site topology of amyloid protein aggregates using multivalent ligands.. Chemical science, 12 (25), 8892-8899. https://doi.org/10.1039/d1sc01263k
A key process in the development of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases is the aggregation of proteins to produce fibrillary aggregates with a cross β-sheet structure, amyloid. The development of reagents that can bind these aggregates with high affinity and selectivity has potential for early disease diagnosis. By linking two benzothiazole aniline (BTA) head groups with different length polyethylene glycol (PEG) spacers, fluorescent probes that bind amyloid fibrils with low nanomolar affinity have been obtained. Dissociation constants measured for interaction with Aβ, α-synuclein and tau fibrils show that the length of the linker determines binding affinity and selectivity. These compounds were successfully used to image α-synuclein aggregates <i>in vitro</i> and in the post-mortem brain tissue of patients with Parkinson's disease. The results demonstrate that multivalent ligands offer a powerful approach to obtain high affinity, selective reagents to bind the fibrillary aggregates that form in neurodegenerative disease.
External DOI: https://doi.org/10.1039/d1sc01263k
This record's URL: https://www.repository.cam.ac.uk/handle/1810/326792
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/