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SAR by kinetics for drug discovery in protein misfolding diseases

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 (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
organization
publishing date
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 Acad Sciences
external identifiers
  • 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
2019-05-21 04:14:03
@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},
  keyword      = {Alzheimer's disease,Amyloid beta peptide,Chemical kinetics,Protein aggregation,Protein misfolding},
  language     = {eng},
  number       = {41},
  pages        = {10245--10250},
  publisher    = {National Acad 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},
  volume       = {115},
  year         = {2018},
}