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SAR by kinetics for drug discovery in protein misfolding diseases

To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure−activity relationship (SAR) approach based on chemical kinetics to estimate quantitativ...

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Autores principales: Chia, Sean, Habchi, Johnny, Michaels, Thomas C. T., Cohen, Samuel I. A., Linse, Sara, Dobson, Christopher M., Knowles, Tuomas P. J., Vendruscolo, Michele
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187117/
https://www.ncbi.nlm.nih.gov/pubmed/30257937
http://dx.doi.org/10.1073/pnas.1807884115
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author Chia, Sean
Habchi, Johnny
Michaels, Thomas C. T.
Cohen, Samuel I. A.
Linse, Sara
Dobson, Christopher M.
Knowles, Tuomas P. J.
Vendruscolo, Michele
author_facet Chia, Sean
Habchi, Johnny
Michaels, Thomas C. T.
Cohen, Samuel I. A.
Linse, Sara
Dobson, Christopher M.
Knowles, Tuomas P. J.
Vendruscolo, Michele
author_sort Chia, Sean
collection PubMed
description To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure−activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aβ), which we then exploit to optimize starting compounds to curtail Aβ oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of Aβ oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers.
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spelling pubmed-61871172018-10-15 SAR by kinetics for drug discovery in protein misfolding diseases Chia, Sean Habchi, Johnny Michaels, Thomas C. T. Cohen, Samuel I. A. Linse, Sara Dobson, Christopher M. Knowles, Tuomas P. J. Vendruscolo, Michele Proc Natl Acad Sci U S A Physical Sciences To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure−activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aβ), which we then exploit to optimize starting compounds to curtail Aβ oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of Aβ oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers. National Academy of Sciences 2018-10-09 2018-09-26 /pmc/articles/PMC6187117/ /pubmed/30257937 http://dx.doi.org/10.1073/pnas.1807884115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Physical Sciences
Chia, Sean
Habchi, Johnny
Michaels, Thomas C. T.
Cohen, Samuel I. A.
Linse, Sara
Dobson, Christopher M.
Knowles, Tuomas P. J.
Vendruscolo, Michele
SAR by kinetics for drug discovery in protein misfolding diseases
title SAR by kinetics for drug discovery in protein misfolding diseases
title_full SAR by kinetics for drug discovery in protein misfolding diseases
title_fullStr SAR by kinetics for drug discovery in protein misfolding diseases
title_full_unstemmed SAR by kinetics for drug discovery in protein misfolding diseases
title_short SAR by kinetics for drug discovery in protein misfolding diseases
title_sort sar by kinetics for drug discovery in protein misfolding diseases
topic Physical Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187117/
https://www.ncbi.nlm.nih.gov/pubmed/30257937
http://dx.doi.org/10.1073/pnas.1807884115
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