Three Distinct Binding Modes Govern High-Affinity Ligand Interactions with Amyloid Fibrils.
- 1Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
Abstract
Fibrillar protein aggregates are a defining feature of neurodegenerative diseases and represent attractive biomarkers and therapeutic targets. However, the rational design of small-molecule ligands and probes targeting these aggregates is limited by a poor understanding of how ligands bind to amyloid fibrils. This work outlines an experimental approach to determine the binding mode of ligands to amyloid fibrils using previously overlooked information contained within standard binding assays. Using a mathematical framework to analyze binding behavior, three distinct high-affinity binding modes were identified: discrete, overlapping, and interacting binding. Reanalysis of published binding data indicates that these binding modes are widespread among common amyloid-binding ligand scaffolds. Two ligands were designed using principles informed by these binding modes, yielding improved binding affinities and characteristic fluorescence responses. These findings establish a practical framework for determining how small molecules bind amyloid fibrils using straightforward binding assays and for guiding the design of future fibril-binding ligands and probes.
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BibTeX
@article{chisholm2026three,
title = {{Three Distinct Binding Modes Govern High-Affinity Ligand Interactions with Amyloid Fibrils.}},
author = {Timothy S Chisholm},
journal = {Biochemistry},
year = {2026},
month = oct,
doi = {10.1021/acs.biochem.6c00489},
url = {https://europepmc.org/article/MED/42899593},
note = {CC BY},
}
RIS
TY - JOUR
TI - Three Distinct Binding Modes Govern High-Affinity Ligand Interactions with Amyloid Fibrils.
AU - Timothy S Chisholm
PY - 2026
DA - 2026/10/01
JO - Biochemistry
DO - 10.1021/acs.biochem.6c00489
UR - https://europepmc.org/article/MED/42899593
AB - Fibrillar protein aggregates are a defining feature of neurodegenerative diseases and represent attractive biomarkers and therapeutic targets. However, the rational design of small-molecule ligands and probes targeting these aggregates is limited by a poor understanding of how ligands bind to amyloid fibrils. This work outlines an experimental approach to determine the binding mode of ligands to amyloid fibrils using previously overlooked information contained within standard binding assays. Using a mathematical framework to analyze binding behavior, three distinct high-affinity binding modes were identified: discrete, overlapping, and interacting binding. Reanalysis of published binding data indicates that these binding modes are widespread among common amyloid-binding ligand scaffolds. Two ligands were designed using principles informed by these binding modes, yielding improved binding affinities and characteristic fluorescence responses. These findings establish a practical framework for determining how small molecules bind amyloid fibrils using straightforward binding assays and for guiding the design of future fibril-binding ligands and probes.
SN - 0006-2960
SN - 1520-4995
ER -