Although the evidence is still limited, a growing body of research suggests music may have beneficial effects for diseases such as Parkinson’s.
Image credit: Shutterstock/agsandrew.
New Research In
Physical Sciences
Featured Portals
Articles by Topic
Biological Sciences
Featured Portals
Articles by Topic
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.
References
Log in using your username and password
Log in through your institution
You may be able to gain access using your login credentials for your institution. Contact your library if you do not have a username and password.
If your organization uses OpenAthens, you can log in using your OpenAthens username and password. To check if your institution is supported, please see this list. Contact your library for more details.
Purchase access
You may purchase access to this article. This will require you to create an account if you don't already have one.
Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors
Sign up for Article Alerts
Article Classifications
- Biological Sciences
- Biophysics and Computational Biology
- Physical Sciences
- Chemistry
Jump to section
- Article
- 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
- References
- Figures & SI
- Info & Metrics
You May Also be Interested in
Biomedical communities and journals need to standardize nomenclature of gene products to enhance accuracy in scientific and public communication.
Image credit: Shutterstock/greenbutterfly.
Shapeshifting designs could have wide-ranging pharmaceutical and biomedical applications in coming years.
Image credit: Acacia Dishman/Medical College of Wisconsin.
Amanda Rodewald, Ivan Rudik, and Catherine Kling talk about the hazards of ozone pollution to birds.
CRISPR-Cas9 gene editing can improve the effectiveness of spermatogonial stem cell transplantation in mice and livestock, a study finds.
Image credit: Jon M. Oatley.