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Inhibitors of protein aggregation and toxicity

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Inhibitors of protein aggregation and toxicity. / Amijee, Hozefa; Madine, Jill; Middleton, David A et al.
In: Biochemical Society Transactions, Vol. 37, No. Pt 4, 08.2009, p. 692-6.

Research output: Contribution to Journal/Magazine › Journal article › peer-review

Harvard

Amijee, H, Madine, J, Middleton, DA & Doig, AJ 2009, 'Inhibitors of protein aggregation and toxicity', Biochemical Society Transactions, vol. 37, no. Pt 4, pp. 692-6. https://doi.org/10.1042/BST0370692

APA

Amijee, H., Madine, J., Middleton, D. A., & Doig, A. J. (2009). Inhibitors of protein aggregation and toxicity. Biochemical Society Transactions, 37(Pt 4), 692-6. https://doi.org/10.1042/BST0370692

Vancouver

Amijee H, Madine J, Middleton DA, Doig AJ. Inhibitors of protein aggregation and toxicity. Biochemical Society Transactions. 2009 Aug;37(Pt 4):692-6. doi: 10.1042/BST0370692

Author

Amijee, Hozefa ; Madine, Jill ; Middleton, David A et al. / Inhibitors of protein aggregation and toxicity. In: Biochemical Society Transactions. 2009 ; Vol. 37, No. Pt 4. pp. 692-6.

Bibtex

@article{4df8430020f142e8be6920f8e1c69bbf,
title = "Inhibitors of protein aggregation and toxicity",
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.",
keywords = "Alzheimer Disease, Amyloid beta-Peptides, Animals, Drug Design, Humans, Magnetic Resonance Spectroscopy, Molecular Structure, Parkinsonian Disorders, Peptide Fragments, Peptides, Protein Folding, alpha-Synuclein",
author = "Hozefa Amijee and Jill Madine and Middleton, {David A} and Doig, {Andrew J}",
year = "2009",
month = aug,
doi = "10.1042/BST0370692",
language = "English",
volume = "37",
pages = "692--6",
journal = "Biochemical Society Transactions",
issn = "0300-5127",
publisher = "Portland Press Ltd.",
number = "Pt 4",

}

RIS

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 -