The aggregation of numerous peptides or proteins has been linked to the onset of disease, including Aβ (amyloid β-peptide) in AD (Alzheimer's disease), asyn (α-synuclein) in Parkinson's disease and amylin in Type 2 diabetes. Diverse amyloidogenic proteins can often be cut down to an SRE (self-recognition element) of as few as five residues that retains the ability to aggregate. SREs can be used as a starting point for aggregation inhibitors. In particular, N-methylated SREs can bind to a target on one side, but have hydrogen-bonding blocked on their methylated face, interfering with further assembly. We applied this strategy to develop Aβ toxicity inhibitors. Our compounds, and a range of compounds from the literature, were compared under the same conditions, using biophysical and toxicity assays. Two N-methylated D-peptide inhibitors with unnatural side chains were the most effective and can reverse Aβ-induced inhibition of LTP (long-term potentiation) at concentrations as low as 10 nM. An SRE in asyn (VAQKTV) was identified using solid-state NMR. When VAQKTV was N-methylated, it was able to disrupt asyn aggregation. N-methylated derivatives of the SRE of amylin are also able to inhibit amylin aggregation.
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August 2009
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Conference Article|
July 22 2009
Inhibitors of protein aggregation and toxicity
Hozefa Amijee;
Hozefa Amijee
*Senexis Limited, Babraham Research Campus, Cambridge CB2 4AT, U.K.
†Manchester Interdisciplinary Biocentre, 131 Princess Street, University of Manchester, Manchester M1 7DN, U.K.
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Jill Madine;
Jill Madine
‡School of Biological Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZB, U.K.
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David A. Middleton;
David A. Middleton
‡School of Biological Sciences, University of Liverpool, Crown Street, Liverpool L69 7ZB, U.K.
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Andrew J. Doig
Andrew J. Doig
1
†Manchester Interdisciplinary Biocentre, 131 Princess Street, University of Manchester, Manchester M1 7DN, U.K.
1To whom correspondence should be addressed (email andrew.doig@manchester.ac.uk).
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Publisher: Portland Press Ltd
Received:
March 12 2009
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem Soc Trans (2009) 37 (4): 692–696.
Article history
Received:
March 12 2009
Citation
Hozefa Amijee, Jill Madine, David A. Middleton, Andrew J. Doig; Inhibitors of protein aggregation and toxicity. Biochem Soc Trans 1 August 2009; 37 (4): 692–696. doi: https://doi.org/10.1042/BST0370692
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