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Roy N. Alcalay, M.D.
"Why do some people who carry genetic mutations associated with Parkinson’s disease (PD) never develop PD while others do?" asks Roy N. Alcalay, M.D., a postdoctoral fellow at the Center for Parkinson’s Disease and Other Movement Disorders...
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Inhibitors of protein aggregation and toxicity.
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Biochem Soc Trans 2009 Aug; 37(Pt 4):692-6
Authors: Hozefa Amijee, Jill Madine, David A Middleton, Andrew J Doig
Senexis Limited, Babraham Research Campus, Cambridge CB2 4AT, UK. andrew.doig@manchester.ac.uk
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.
PMID: 19614577 [PubMed - as supplied by publisher]
