Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors

Thomas C.T. Michaels, Andela Šarić, Georg Meisl, Gabriella T. Heller, Samo Curk, Paolo Arosio, Sara Linse, Christopher M. Dobson, Michele Vendruscolo, Tuomas P.J. Knowles

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)24251-24257
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number39
DOIs
Publication statusPublished - 2020 Sept 29

Subject classification (UKÄ)

  • Biochemistry and Molecular Biology

Free keywords

  • Amyloid
  • Drug discovery
  • Inhibition
  • Mathematical model
  • Molecular mechanism

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