SAR by kinetics for drug discovery in protein misfolding diseases
(2018) In Proceedings of the National Academy of Sciences of the United States of America 115(41). p.10245-10250- Abstract
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 Aâ 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... (More)
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 Aâ 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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- author
- Chia, Sean ; Habchi, Johnny ; Michaels, Thomas C.T. ; Cohen, Samuel I.A. ; Linse, Sara LU ; Dobson, Christopher M. ; Knowles, Tuomas P.J. and Vendruscolo, Michele
- organization
- publishing date
- 2018
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Alzheimer's disease, Amyloid beta peptide, Chemical kinetics, Protein aggregation, Protein misfolding
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 115
- issue
- 41
- pages
- 6 pages
- publisher
- National Academy of Sciences
- external identifiers
-
- pmid:30257937
- scopus:85054709489
- ISSN
- 0027-8424
- DOI
- 10.1073/pnas.1807884115
- language
- English
- LU publication?
- yes
- id
- 0e3609b7-5072-47d5-aac5-7a27b622927f
- date added to LUP
- 2018-10-30 13:23:03
- date last changed
- 2024-04-01 12:20:46
@article{0e3609b7-5072-47d5-aac5-7a27b622927f,
abstract = {{<p>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 Aâ 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.</p>}},
author = {{Chia, Sean and Habchi, Johnny and Michaels, Thomas C.T. and Cohen, Samuel I.A. and Linse, Sara and Dobson, Christopher M. and Knowles, Tuomas P.J. and Vendruscolo, Michele}},
issn = {{0027-8424}},
keywords = {{Alzheimer's disease; Amyloid beta peptide; Chemical kinetics; Protein aggregation; Protein misfolding}},
language = {{eng}},
number = {{41}},
pages = {{10245--10250}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences of the United States of America}},
title = {{SAR by kinetics for drug discovery in protein misfolding diseases}},
url = {{http://dx.doi.org/10.1073/pnas.1807884115}},
doi = {{10.1073/pnas.1807884115}},
volume = {{115}},
year = {{2018}},
}