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Screening of small molecules using the inhibition of oligomer formation in α-synuclein aggregation as a selection parameter

Staats, Roxine ; Michaels, Thomas C.T. ; Flagmeier, Patrick ; Chia, Sean ; Horne, Robert I. ; Habchi, Johnny ; Linse, Sara LU ; Knowles, Tuomas P.J. ; Dobson, Christopher M. and Vendruscolo, Michele (2020) In Communications Chemistry 3(1).
Abstract

The aggregation of α-synuclein is a central event in Parkinsons’s disease and related synucleinopathies. Since pharmacologically targeting this process, however, has not yet resulted in approved disease-modifying treatments, there is an unmet need of developing novel methods of drug discovery. In this context, the use of chemical kinetics has recently enabled accurate quantifications of the microscopic steps leading to the proliferation of protein misfolded oligomers. As these species are highly neurotoxic, effective therapeutic strategies may be aimed at reducing their numbers. Here, we exploit this quantitative approach to develop a screening strategy that uses the reactive flux toward α-synuclein oligomers as a selection parameter.... (More)

The aggregation of α-synuclein is a central event in Parkinsons’s disease and related synucleinopathies. Since pharmacologically targeting this process, however, has not yet resulted in approved disease-modifying treatments, there is an unmet need of developing novel methods of drug discovery. In this context, the use of chemical kinetics has recently enabled accurate quantifications of the microscopic steps leading to the proliferation of protein misfolded oligomers. As these species are highly neurotoxic, effective therapeutic strategies may be aimed at reducing their numbers. Here, we exploit this quantitative approach to develop a screening strategy that uses the reactive flux toward α-synuclein oligomers as a selection parameter. Using this approach, we evaluate the efficacy of a library of flavone derivatives, identifying apigenin as a compound that simultaneously delays and reduces the formation of α-synuclein oligomers. These results demonstrate a compound selection strategy based on the inhibition of the formation of α-synuclein oligomers, which may be key in identifying small molecules in drug discovery pipelines for diseases associated with α-synuclein aggregation.

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Contribution to journal
publication status
published
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Communications Chemistry
volume
3
issue
1
article number
191
publisher
Springer Nature
external identifiers
  • scopus:85097747249
ISSN
2399-3669
DOI
10.1038/s42004-020-00412-y
language
English
LU publication?
yes
id
d7016ba5-f4d7-41ab-98a2-9d32558b47ba
date added to LUP
2021-01-07 13:48:57
date last changed
2021-02-17 08:17:59
@article{d7016ba5-f4d7-41ab-98a2-9d32558b47ba,
  abstract     = {<p>The aggregation of α-synuclein is a central event in Parkinsons’s disease and related synucleinopathies. Since pharmacologically targeting this process, however, has not yet resulted in approved disease-modifying treatments, there is an unmet need of developing novel methods of drug discovery. In this context, the use of chemical kinetics has recently enabled accurate quantifications of the microscopic steps leading to the proliferation of protein misfolded oligomers. As these species are highly neurotoxic, effective therapeutic strategies may be aimed at reducing their numbers. Here, we exploit this quantitative approach to develop a screening strategy that uses the reactive flux toward α-synuclein oligomers as a selection parameter. Using this approach, we evaluate the efficacy of a library of flavone derivatives, identifying apigenin as a compound that simultaneously delays and reduces the formation of α-synuclein oligomers. These results demonstrate a compound selection strategy based on the inhibition of the formation of α-synuclein oligomers, which may be key in identifying small molecules in drug discovery pipelines for diseases associated with α-synuclein aggregation.</p>},
  author       = {Staats, Roxine and Michaels, Thomas C.T. and Flagmeier, Patrick and Chia, Sean and Horne, Robert I. and Habchi, Johnny and Linse, Sara and Knowles, Tuomas P.J. and Dobson, Christopher M. and Vendruscolo, Michele},
  issn         = {2399-3669},
  language     = {eng},
  number       = {1},
  publisher    = {Springer Nature},
  series       = {Communications Chemistry},
  title        = {Screening of small molecules using the inhibition of oligomer formation in α-synuclein aggregation as a selection parameter},
  url          = {http://dx.doi.org/10.1038/s42004-020-00412-y},
  doi          = {10.1038/s42004-020-00412-y},
  volume       = {3},
  year         = {2020},
}