Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors
(2020) In Proceedings of the National Academy of Sciences of the United States of America 117(39). p.24251-24257- 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... (More)
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.
(Less)
- author
- Michaels, Thomas C.T. ; Šarić, Andela ; Meisl, Georg ; Heller, Gabriella T. ; Curk, Samo ; Arosio, Paolo ; Linse, Sara LU ; Dobson, Christopher M. ; Vendruscolo, Michele and Knowles, Tuomas P.J.
- organization
- publishing date
- 2020-09-29
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Amyloid, Drug discovery, Inhibition, Mathematical model, Molecular mechanism
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 117
- issue
- 39
- pages
- 7 pages
- publisher
- National Academy of Sciences
- external identifiers
-
- scopus:85092322411
- pmid:32929030
- ISSN
- 0027-8424
- DOI
- 10.1073/pnas.2006684117
- language
- English
- LU publication?
- yes
- id
- 37f30267-69a9-4e11-af72-87a4f1a329d5
- date added to LUP
- 2020-10-27 13:05:54
- date last changed
- 2024-06-12 22:21:53
@article{37f30267-69a9-4e11-af72-87a4f1a329d5,
abstract = {{<p>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.</p>}},
author = {{Michaels, Thomas C.T. and Šarić, Andela and Meisl, Georg and Heller, Gabriella T. and Curk, Samo and Arosio, Paolo and Linse, Sara and Dobson, Christopher M. and Vendruscolo, Michele and Knowles, Tuomas P.J.}},
issn = {{0027-8424}},
keywords = {{Amyloid; Drug discovery; Inhibition; Mathematical model; Molecular mechanism}},
language = {{eng}},
month = {{09}},
number = {{39}},
pages = {{24251--24257}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences of the United States of America}},
title = {{Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors}},
url = {{http://dx.doi.org/10.1073/pnas.2006684117}},
doi = {{10.1073/pnas.2006684117}},
volume = {{117}},
year = {{2020}},
}