Michaels, TCT;
Saric, A;
Meisl, G;
Heller, GT;
Curk, S;
Arosio, P;
Linse, S;
... Knowles, TPJ; + view all
(2020)
Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors.
Proceedings of the National Academy of Sciences of the United States of America
, 117
(39)
pp. 24251-24257.
10.1073/pnas.2006684117.
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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.
| Type: | Article |
|---|---|
| Title: | Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.2006684117 |
| Publisher version: | https://doi.org/10.1073/pnas.2006684117 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, amyloid, inhibition, drug discovery, mathematical model, molecular mechanism, SMALL-MOLECULE INHIBITORS, PROTEIN AGGREGATION, ALZHEIMERS-DISEASE, SECONDARY NUCLEATION, CHEMICAL-KINETICS, DRUG DISCOVERY, MECHANISMS, POLYMERIZATION, HYPOTHESIS, OLIGOMERS |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Physics and Astronomy |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10135010 |
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