Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Inhibitors of protein aggregation and toxicity
AU - Amijee, Hozefa
AU - Madine, Jill
AU - Middleton, David A
AU - Doig, Andrew J
PY - 2009/8
Y1 - 2009/8
N2 - 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.
AB - 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.
KW - Alzheimer Disease
KW - Amyloid beta-Peptides
KW - Animals
KW - Drug Design
KW - Humans
KW - Magnetic Resonance Spectroscopy
KW - Molecular Structure
KW - Parkinsonian Disorders
KW - Peptide Fragments
KW - Peptides
KW - Protein Folding
KW - alpha-Synuclein
U2 - 10.1042/BST0370692
DO - 10.1042/BST0370692
M3 - Journal article
C2 - 19614577
VL - 37
SP - 692
EP - 696
JO - Biochemical Society Transactions
JF - Biochemical Society Transactions
SN - 0300-5127
IS - Pt 4
ER -