{"volume":117,"intvolume":"       117","date_updated":"2021-11-26T08:59:06Z","scopus_import":"1","type":"journal_article","oa":1,"publication_identifier":{"issn":["0027-8424"],"eissn":["1091-6490"]},"_id":"10347","citation":{"ista":"Michaels TCT, Šarić A, Meisl G, Heller GT, Curk S, Arosio P, Linse S, Dobson CM, Vendruscolo M, Knowles TPJ. 2020. Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors. Proceedings of the National Academy of Sciences. 117(39), 24251–24257.","ieee":"T. C. T. Michaels <i>et al.</i>, “Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors,” <i>Proceedings of the National Academy of Sciences</i>, vol. 117, no. 39. National Academy of Sciences, pp. 24251–24257, 2020.","apa":"Michaels, T. C. T., Šarić, A., Meisl, G., Heller, G. T., Curk, S., Arosio, P., … Knowles, T. P. J. (2020). Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors. <i>Proceedings of the National Academy of Sciences</i>. National Academy of Sciences. <a href=\"https://doi.org/10.1073/pnas.2006684117\">https://doi.org/10.1073/pnas.2006684117</a>","chicago":"Michaels, Thomas C. T., Anđela Šarić, Georg Meisl, Gabriella T. Heller, Samo Curk, Paolo Arosio, Sara Linse, Christopher M. Dobson, Michele Vendruscolo, and Tuomas P. J. Knowles. “Thermodynamic and Kinetic Design Principles for Amyloid-Aggregation Inhibitors.” <i>Proceedings of the National Academy of Sciences</i>. National Academy of Sciences, 2020. <a href=\"https://doi.org/10.1073/pnas.2006684117\">https://doi.org/10.1073/pnas.2006684117</a>.","ama":"Michaels TCT, Šarić A, Meisl G, et al. Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors. <i>Proceedings of the National Academy of Sciences</i>. 2020;117(39):24251-24257. doi:<a href=\"https://doi.org/10.1073/pnas.2006684117\">10.1073/pnas.2006684117</a>","mla":"Michaels, Thomas C. T., et al. “Thermodynamic and Kinetic Design Principles for Amyloid-Aggregation Inhibitors.” <i>Proceedings of the National Academy of Sciences</i>, vol. 117, no. 39, National Academy of Sciences, 2020, pp. 24251–57, doi:<a href=\"https://doi.org/10.1073/pnas.2006684117\">10.1073/pnas.2006684117</a>.","short":"T.C.T. Michaels, A. Šarić, G. Meisl, G.T. Heller, S. Curk, P. Arosio, S. Linse, C.M. Dobson, M. Vendruscolo, T.P.J. Knowles, Proceedings of the National Academy of Sciences 117 (2020) 24251–24257."},"main_file_link":[{"open_access":"1","url":"https://www.biorxiv.org/content/10.1101/2020.02.22.960716"}],"extern":"1","status":"public","author":[{"last_name":"Michaels","first_name":"Thomas C. T.","full_name":"Michaels, Thomas C. T."},{"id":"bf63d406-f056-11eb-b41d-f263a6566d8b","first_name":"Anđela","last_name":"Šarić","orcid":"0000-0002-7854-2139","full_name":"Šarić, Anđela"},{"full_name":"Meisl, Georg","last_name":"Meisl","first_name":"Georg"},{"first_name":"Gabriella T.","last_name":"Heller","full_name":"Heller, Gabriella T."},{"first_name":"Samo","last_name":"Curk","full_name":"Curk, Samo"},{"full_name":"Arosio, Paolo","last_name":"Arosio","first_name":"Paolo"},{"full_name":"Linse, Sara","last_name":"Linse","first_name":"Sara"},{"last_name":"Dobson","first_name":"Christopher M.","full_name":"Dobson, Christopher M."},{"full_name":"Vendruscolo, Michele","last_name":"Vendruscolo","first_name":"Michele"},{"last_name":"Knowles","first_name":"Tuomas P. J.","full_name":"Knowles, Tuomas P. J."}],"article_processing_charge":"No","publication_status":"published","article_type":"original","page":"24251-24257","publisher":"National Academy of Sciences","publication":"Proceedings of the National Academy of Sciences","oa_version":"Published Version","issue":"39","month":"09","day":"14","language":[{"iso":"eng"}],"title":"Thermodynamic and kinetic design principles for amyloid-aggregation inhibitors","acknowledgement":"We acknowledge support from Peterhouse, Cambridge (T.C.T.M.); the Swiss National Science Foundation (T.C.T.M.); the Royal Society (A.S. and S.C.); the Academy of Medical Sciences (A.S.); Sidney Sussex College, Cambridge (G.M.); Newnham College, Cambridge (G.T.H.); the Wellcome Trust (T.P.J.K.); the Cambridge Center for Misfolding Diseases (T.P.J.K. and M.V.); the Biotechnology and Biological Sciences Research Council (T.P.J.K.); the Frances and Augustus Newman Foundation (T.P.J.K.); and the Synapsis Foundation for Alzheimer’s disease (P.A.). The research leading to these results has received funding from the European Research Council (ERC) under the European Union’s Seventh Framework Program (FP7/2007-2013) through the ERC Grant PhysProt (Agreement 337969).","quality_controlled":"1","date_created":"2021-11-26T07:48:27Z","abstract":[{"lang":"eng","text":"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."}],"date_published":"2020-09-14T00:00:00Z","external_id":{"pmid":["32929030"]},"keyword":["multidisciplinary"],"user_id":"8b945eb4-e2f2-11eb-945a-df72226e66a9","doi":"10.1073/pnas.2006684117","year":"2020","pmid":1}