Inhibitors of protein aggregation and toxicity

Amijee, Hozefa and Madine, Jill and Middleton, David A and Doig, Andrew J (2009) Inhibitors of protein aggregation and toxicity. Biochemical Society Transactions, 37 (Pt 4). pp. 692-6. ISSN 0300-5127

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Abstract

The aggregation of numerous peptides or proteins has been linked to the onset of disease, including Abeta (amyloid beta-peptide) in AD (Alzheimer's disease), asyn (alpha-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 Abeta 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 Abeta-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.

Item Type:
Journal Article
Journal or Publication Title:
Biochemical Society Transactions
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1303
Subjects:
ID Code:
66268
Deposited By:
Deposited On:
17 Sep 2013 08:03
Refereed?:
Yes
Published?:
Published
Last Modified:
07 Apr 2020 02:34