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Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer's disease

Habchi, Johnny; Chia, Sean; Limbocker, Ryan; Mannini, Benedetta; Ahn, Minkoo; Perni, Michele; Hansson, Oskar LU ; Arosio, Paolo; Kumita, Janet R and Challa, Pavan Kumar, et al. (2017) In Proceedings of the National Academy of Sciences of the United States of America 114(2). p.200-208
Abstract

The aggregation of the 42-residue form of the amyloid-β peptide (Aβ42) is a pivotal event in Alzheimer's disease (AD). The use of chemical kinetics has recently enabled highly accurate quantifications of the effects of small molecules on specific microscopic steps in Aβ42 aggregation. Here, we exploit this approach to develop a rational drug discovery strategy against Aβ42 aggregation that uses as a readout the changes in the nucleation and elongation rate constants caused by candidate small molecules. We thus identify a pool of compounds that target specific microscopic steps in Aβ42 aggregation. We then test further these small molecules in human cerebrospinal fluid and in a Caenorhabditis elegans model of AD. Our results show that... (More)

The aggregation of the 42-residue form of the amyloid-β peptide (Aβ42) is a pivotal event in Alzheimer's disease (AD). The use of chemical kinetics has recently enabled highly accurate quantifications of the effects of small molecules on specific microscopic steps in Aβ42 aggregation. Here, we exploit this approach to develop a rational drug discovery strategy against Aβ42 aggregation that uses as a readout the changes in the nucleation and elongation rate constants caused by candidate small molecules. We thus identify a pool of compounds that target specific microscopic steps in Aβ42 aggregation. We then test further these small molecules in human cerebrospinal fluid and in a Caenorhabditis elegans model of AD. Our results show that this strategy represents a powerful approach to identify systematically small molecule lead compounds, thus offering an appealing opportunity to reduce the attrition problem in drug discovery.

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publication status
published
subject
keywords
Alzheimer's disease, Amyloid-β peptide, Drug discovery, Protein aggregation, Protein misfolding
in
Proceedings of the National Academy of Sciences of the United States of America
volume
114
issue
2
pages
200 - 208
publisher
National Acad Sciences
external identifiers
  • scopus:85009348250
  • wos:000391439300012
ISSN
0027-8424
DOI
10.1073/pnas.1615613114
language
English
LU publication?
yes
id
4c250a06-3b4f-49e1-80de-edad8cb6cbee
date added to LUP
2017-02-28 14:45:30
date last changed
2018-01-07 11:53:13
@article{4c250a06-3b4f-49e1-80de-edad8cb6cbee,
  abstract     = {<p>The aggregation of the 42-residue form of the amyloid-β peptide (Aβ42) is a pivotal event in Alzheimer's disease (AD). The use of chemical kinetics has recently enabled highly accurate quantifications of the effects of small molecules on specific microscopic steps in Aβ42 aggregation. Here, we exploit this approach to develop a rational drug discovery strategy against Aβ42 aggregation that uses as a readout the changes in the nucleation and elongation rate constants caused by candidate small molecules. We thus identify a pool of compounds that target specific microscopic steps in Aβ42 aggregation. We then test further these small molecules in human cerebrospinal fluid and in a Caenorhabditis elegans model of AD. Our results show that this strategy represents a powerful approach to identify systematically small molecule lead compounds, thus offering an appealing opportunity to reduce the attrition problem in drug discovery.</p>},
  author       = {Habchi, Johnny and Chia, Sean and Limbocker, Ryan and Mannini, Benedetta and Ahn, Minkoo and Perni, Michele and Hansson, Oskar and Arosio, Paolo and Kumita, Janet R and Challa, Pavan Kumar 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-β peptide,Drug discovery,Protein aggregation,Protein misfolding},
  language     = {eng},
  month        = {01},
  number       = {2},
  pages        = {200--208},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer's disease},
  url          = {http://dx.doi.org/10.1073/pnas.1615613114},
  volume       = {114},
  year         = {2017},
}