Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors.
Proc Natl Acad Sci U S A
; 117(39): 24251-24257, 2020 09 29.
Article
in En
| MEDLINE
| ID: mdl-32929030
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein Aggregation, Pathological
/
Amyloid
/
Models, Chemical
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2020
Document type:
Article
Affiliation country:
United kingdom