UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

Habchi, J; Chia, S; Limbocker, R; Mannini, B; Ahn, M; Perni, M; Hansson, O; ... Vendruscolo, M; + view all (2017) Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease. Proceedings of the National Academy of Sciences , 114 (2) E200-E208. 10.1073/pnas.1615613114. Green open access

[thumbnail of Ahn_Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease_VoR.pdf]
Preview
Text
Ahn_Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease_VoR.pdf - Published Version

Download (3MB) | Preview

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 read-out 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.

Type: Article
Title: Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1615613114
Publisher version: https://doi.org/10.1073/pnas.1615613114
Language: English
Additional information: Freely available online through the PNAS open access option.
Keywords: Alzheimer’s disease, amyloid-β peptide, protein misfolding, drug discovery, protein aggregation
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10072363
Downloads since deposit
44Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item