Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors

Autor:	Paolo Arosio, Sara Linse, Gabriella T. Heller, Andela Saric, Michele Vendruscolo, Christopher M. Dobson, Tuomas P. J. Knowles, Thomas C. T. Michaels, Samo Curk, Georg Meisl
Rok vydání:	2020
Předmět:	Amyloid Multidisciplinary Drug discovery Chemistry Design elements and principles Biological Sciences Protein Aggregation Pathological Kinetics Models Chemical Computational chemistry Drug Design Amyloid aggregation Molecular mechanism Thermodynamics Molecular Targeted Therapy
Zdroj:	Proc Natl Acad Sci U S A
ISSN:	1091-6490 0027-8424
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::16ef5f65e5dea59089c72857e7e6bb61 https://doi.org/10.1073/pnas.2006684117 Zobrazit plný text záznamu