Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors.

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.

authors

Michaels TCT,Šarić A,Meisl G,Heller GT,Curk S,Arosio P,Linse S,Dobson CM,Vendruscolo M,Knowles TPJ

doi

10.1073/pnas.2006684117

subject

Has Abstract

pub_date

2020-09-29 00:00:00

pages

24251-24257

issue

39

eissn

0027-8424

issn

1091-6490

pii

2006684117

journal_volume

117

pub_type

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