Inhibitors of protein aggregation and toxicity.
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.
Amijee
Hozefa
H
Senexis Limited, Babraham Research Campus, Cambridge CB2 4AT, UK. andrew.doig@manchester.ac.uk
Madine
Jill
J
Middleton
David A
DA
Doig
Andrew J
AJ
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry; D000818:Animals; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D020734:Parkinsonian Disorders / Q000188:drug therapy; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017510:Protein Folding / Q000187:drug effects; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000737:chemistry
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; D051844:alpha-Synuclein