Mapping the binding site topology of amyloid protein aggregates using multivalent ligands.

Autor:	Sanna E; Department of Chemistry, University of Cambridge Lensfield Road Cambridge CB2 1EW UK herchelsmith.orgchem@ch.cam.ac.uk., Rodrigues M; Department of Chemistry, University of Cambridge Lensfield Road Cambridge CB2 1EW UK herchelsmith.orgchem@ch.cam.ac.uk., Fagan SG; Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge Cambridge CB2 0AH UK., Chisholm TS; Department of Chemistry, University of Cambridge Lensfield Road Cambridge CB2 1EW UK herchelsmith.orgchem@ch.cam.ac.uk., Kulenkampff K; Department of Chemistry, University of Cambridge Lensfield Road Cambridge CB2 1EW UK herchelsmith.orgchem@ch.cam.ac.uk., Klenerman D; Department of Chemistry, University of Cambridge Lensfield Road Cambridge CB2 1EW UK herchelsmith.orgchem@ch.cam.ac.uk., Spillantini MG; Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge Cambridge CB2 0AH UK., Aigbirhio FI; Department of Clinical Neuroscience, Wolfson Brain Imaging Centre, University of Cambridge CB2 0QQ UK., Hunter CA; Department of Chemistry, University of Cambridge Lensfield Road Cambridge CB2 1EW UK herchelsmith.orgchem@ch.cam.ac.uk.
Jazyk:	angličtina
Zdroj:	Chemical science [Chem Sci] 2021 Jun 07; Vol. 12 (25), pp. 8892-8899. Date of Electronic Publication: 2021 Jun 07 (Print Publication: 2021).
DOI:	10.1039/d1sc01263k
Abstrakt:	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 in vitro 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. Competing Interests: There are no conflicts to declare. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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