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Proc Natl Acad Sci U S A. 2017 Jan 10;114(2):E200-E208. doi: 10.1073/pnas.1615613114. Epub 2016 Dec 23.

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

Author information

1
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
2
Department of Clinical Sciences, Lund University, 221 00 Lund, Sweden.
3
Memory Clinic, Skåne University Hospital, 205 02 Malmo, Sweden.
4
Department of Biochemistry & Structural Biology, Center for Molecular Protein Science, Lund University, 221 00 Lund, Sweden.
5
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; mv245@cam.ac.uk tpjk2@cam.ac.uk cmd44@cam.ac.uk.

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.

KEYWORDS:

Alzheimer’s disease; amyloid-β peptide; drug discovery; protein aggregation; protein misfolding

PMID:
28011763
PMCID:
PMC5240708
DOI:
10.1073/pnas.1615613114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Part of the work described in this paper has been the subject of a patent application filed by Cambridge Enterprise, a wholly owned subsidiary of the University of Cambridge (now licensed to Wren Therapeutics Ltd., where M.V. is Chief Scientific Officer; S.I.A.C., C.M.D., and M.V. are members of the Board of Directors; and S.I.A.C., S.L., C.M.D., and T.P.J.K. are consultants).

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