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Edited by Alexander M. Klibanov, Massachusetts Institute of Technology, Cambridge, MA, and approved August 17, 2020 (received for review April 8, 2020)
Significance
Developing effective strategies against human disorders linked with amyloid aggregation, including Alzheimer’s and Parkinson’s diseases, has proven to be difficult. A major reason is that traditional drug-discovery methods are poorly suited to deal with complex reaction networks such as those in involved in the aggregation process. It therefore remains challenging to identify suitable targets for drug development. To overcome this difficulty, we lay out here a general theory for inhibition of protein aggregation into amyloid fibrils, which uncovers quantitative thermodynamic and kinetic design principles to guide the rational search and optimization of effective inhibitors of fibril formation.
Abstract
Understanding the mechanism of action of compounds capable of inhibiting amyloid-fibril formation is critical to the development of potential therapeutics against protein-misfolding diseases. A fundamental challenge for progress is the range of possible target species and the disparate timescales involved, since the aggregating proteins are simultaneously the reactants, products, intermediates, and catalysts of the reaction. It is a complex problem, therefore, to choose the states of the aggregating proteins that should be bound by the compounds to achieve the most potent inhibition. We present here a comprehensive kinetic theory of amyloid-aggregation inhibition that reveals the fundamental thermodynamic and kinetic signatures characterizing effective inhibitors by identifying quantitative relationships between the aggregation and binding rate constants. These results provide general physical laws to guide the design and optimization of inhibitors of amyloid-fibril formation, revealing in particular the important role of on-rates in the binding of the inhibitors.
Footnotes
- ↵1To whom correspondence may be addressed. Email: mv245{at}cam.ac.uk or tpjk2{at}cam.ac.uk.
Author contributions: T.C.T.M., S.L., C.M.D., M.V., and T.P.J.K. designed research; T.C.T.M. performed research; G.T.H. contributed new reagents/analytic tools; T.C.T.M. analyzed data; and T.C.T.M., A.S., G.M., G.T.H., S.C., P.A., S.L., C.M.D., M.V., and T.P.J.K. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2006684117/-/DCSupplemental.
Data Availability.
All study data are included in the article and SI Appendix.
Published under the PNAS license.
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Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors
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Article Classifications
- Biological Sciences
- Biophysics and Computational Biology
- Physical Sciences
- Chemistry
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- Abstract
- Aggregation Kinetics in the Presence of an Inhibitor
- Integrated Rate Laws for Inhibited-Aggregation Kinetics
- The Interplay between Kinetics and Thermodynamics Generates a Rich Inhibition-Phase Behavior
- Physical Design Principles for Effective Inhibitors and Illustrative Examples on Experimental Data
- Summary and Outlook
- Data Availability.
- Acknowledgments
- Footnotes
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