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Quantifying species-specific binding affinities of transthyretin aggregation inhibitors
Xun Sun1, H Jane Dyson1, Peter E Wright1
1Department of Integrative Structural and Computational Biology and Skaggs Institute of Chemical Biology, Scripps Research, La Jolla, CA, USA.
Biophysical Reports
|June 19, 2026
Summary
A new method quantifies how well drugs bind to transthyretin (TTR) amyloidosis targets. This approach reveals that acidic conditions significantly enhance drug binding to TTR tetramers and monomers, aiding inhibitor design.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Discovery
Background:
- Transthyretin (TTR) amyloidosis results from pathogenic TTR aggregate deposition.
- TTR aggregation involves tetramer dissociation into misfolding monomers.
- Existing methods struggle to quantify inhibitor binding to transient TTR species.
Purpose of the Study:
- Develop a quantitative method to determine species-specific binding affinities of inhibitors to TTR.
- Analyze inhibitor binding under various conditions, including acidic pH.
- Provide mechanistic insights for designing improved TTR aggregation inhibitors.
Main Methods:
- Utilized population-resolved 19F-NMR aggregation assays.
- Developed a novel quantitative analysis to extract binding affinities.
- Applied the method to diflunisal and designed peptide inhibitors.
Main Results:
- Quantified binding affinities of diflunisal to TTR tetramers and monomers.
- Observed significantly enhanced binding at acidic pH (2-fold for tetramer, 15-fold for monomer).
- Demonstrated that concatenated peptides show a 2-fold increase in binding affinity compared to mixed peptides.
Conclusions:
- The developed method allows direct, quantitative comparison of inhibitor binding to different TTR species.
- Acidic conditions enhance the binding of small molecules and peptides to TTR.
- This quantitative approach is crucial for optimizing TTR aggregation inhibitors for therapeutic development.
