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Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors

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. (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.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
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 Acad Sciences
external identifiers
  • pmid:32929030
  • scopus:85092322411
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
2021-02-17 05:42:25
@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},
  language     = {eng},
  month        = {09},
  number       = {39},
  pages        = {24251--24257},
  publisher    = {National Acad 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},
}