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Design of an N-methylated peptide inhibitor of alpha-synuclein aggregation guided by solid-state NMR

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Design of an N-methylated peptide inhibitor of alpha-synuclein aggregation guided by solid-state NMR. / Madine, Jillian; Doig, Andrew J; Middleton, David A.

In: Journal of the American Chemical Society, Vol. 130, No. 25, 25.06.2008, p. 7873-81.

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Madine, J, Doig, AJ & Middleton, DA 2008, 'Design of an N-methylated peptide inhibitor of alpha-synuclein aggregation guided by solid-state NMR', Journal of the American Chemical Society, vol. 130, no. 25, pp. 7873-81. https://doi.org/10.1021/ja075356q

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Madine, Jillian ; Doig, Andrew J ; Middleton, David A. / Design of an N-methylated peptide inhibitor of alpha-synuclein aggregation guided by solid-state NMR. In: Journal of the American Chemical Society. 2008 ; Vol. 130, No. 25. pp. 7873-81.

Bibtex

@article{92f3b874790e412691e2bb55395b56bb,
title = "Design of an N-methylated peptide inhibitor of alpha-synuclein aggregation guided by solid-state NMR",
abstract = "Many neurodegenerative diseases are associated with the aggregation of misfolded proteins into amyloid oligomers or fibrils that are deposited as pathological lesions within areas of the brain. An attractive therapeutic strategy for preventing or ameliorating amyloid formation is to identify agents that inhibit the onset or propagation of protein aggregation. Here we demonstrate how solid-state nuclear magnetic resonance (ssNMR) may be used to identify key residues within amyloidogenic protein sequences that may be targeted to inhibit the aggregation of the host protein. For alpha-synuclein, the major protein component of Lewy bodies associated with Parkinson's disease, we have used a combination of ssNMR and biochemical data to identify the key region for self-aggregation of the protein as residues 77-82 (VAQKTV). We used our new structural information to design a peptide derived from residues 77 to 82 of alpha-synuclein with an N-methyl group at the C-terminal residue, which was able to disrupt the aggregation of alpha-synuclein. Thus, we have shown how structural data obtained from ssNMR can guide the design of modified peptides for use as amyloid inhibitors, as a primary step toward developing therapeutic compounds for prevention and/or treatment of amyloid diseases.",
keywords = "Amino Acid Sequence, Drug Design, Humans, Magnetic Resonance Spectroscopy, Methylation, Molecular Sequence Data, Peptides, Solubility, alpha-Synuclein",
author = "Jillian Madine and Doig, {Andrew J} and Middleton, {David A}",
year = "2008",
month = jun,
day = "25",
doi = "10.1021/ja075356q",
language = "English",
volume = "130",
pages = "7873--81",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "AMER CHEMICAL SOC",
number = "25",

}

RIS

TY - JOUR

T1 - Design of an N-methylated peptide inhibitor of alpha-synuclein aggregation guided by solid-state NMR

AU - Madine, Jillian

AU - Doig, Andrew J

AU - Middleton, David A

PY - 2008/6/25

Y1 - 2008/6/25

N2 - Many neurodegenerative diseases are associated with the aggregation of misfolded proteins into amyloid oligomers or fibrils that are deposited as pathological lesions within areas of the brain. An attractive therapeutic strategy for preventing or ameliorating amyloid formation is to identify agents that inhibit the onset or propagation of protein aggregation. Here we demonstrate how solid-state nuclear magnetic resonance (ssNMR) may be used to identify key residues within amyloidogenic protein sequences that may be targeted to inhibit the aggregation of the host protein. For alpha-synuclein, the major protein component of Lewy bodies associated with Parkinson's disease, we have used a combination of ssNMR and biochemical data to identify the key region for self-aggregation of the protein as residues 77-82 (VAQKTV). We used our new structural information to design a peptide derived from residues 77 to 82 of alpha-synuclein with an N-methyl group at the C-terminal residue, which was able to disrupt the aggregation of alpha-synuclein. Thus, we have shown how structural data obtained from ssNMR can guide the design of modified peptides for use as amyloid inhibitors, as a primary step toward developing therapeutic compounds for prevention and/or treatment of amyloid diseases.

AB - Many neurodegenerative diseases are associated with the aggregation of misfolded proteins into amyloid oligomers or fibrils that are deposited as pathological lesions within areas of the brain. An attractive therapeutic strategy for preventing or ameliorating amyloid formation is to identify agents that inhibit the onset or propagation of protein aggregation. Here we demonstrate how solid-state nuclear magnetic resonance (ssNMR) may be used to identify key residues within amyloidogenic protein sequences that may be targeted to inhibit the aggregation of the host protein. For alpha-synuclein, the major protein component of Lewy bodies associated with Parkinson's disease, we have used a combination of ssNMR and biochemical data to identify the key region for self-aggregation of the protein as residues 77-82 (VAQKTV). We used our new structural information to design a peptide derived from residues 77 to 82 of alpha-synuclein with an N-methyl group at the C-terminal residue, which was able to disrupt the aggregation of alpha-synuclein. Thus, we have shown how structural data obtained from ssNMR can guide the design of modified peptides for use as amyloid inhibitors, as a primary step toward developing therapeutic compounds for prevention and/or treatment of amyloid diseases.

KW - Amino Acid Sequence

KW - Drug Design

KW - Humans

KW - Magnetic Resonance Spectroscopy

KW - Methylation

KW - Molecular Sequence Data

KW - Peptides

KW - Solubility

KW - alpha-Synuclein

UR - http://www.scopus.com/inward/record.url?scp=45749101292&partnerID=8YFLogxK

U2 - 10.1021/ja075356q

DO - 10.1021/ja075356q

M3 - Journal article

C2 - 18510319

VL - 130

SP - 7873

EP - 7881

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 25

ER -