Amphiphilic oligoamide α-helix peptidomimetics inhibit islet amyloid polypeptide aggregation

Oleg V. Kulikov; Sunil Kumar; Mazin Magzoub; Peter C. Knipe; Ishu Saraogi; Sam Thompson; Andrew D. Miranker; Andrew D. Hamilton

doi:10.1016/j.tetlet.2015.02.132

Amphiphilic oligoamide α-helix peptidomimetics inhibit islet amyloid polypeptide aggregation

Oleg V. Kulikov, Sunil Kumar, Mazin Magzoub, Peter C. Knipe, Ishu Saraogi, Sam Thompson, Andrew D. Miranker, Andrew D. Hamilton

Research output: Contribution to journal › Article › peer-review

Abstract

Abstract The abnormal deposition of proteins as insoluble plaques is associated with many diseases, including Alzheimer's, Parkinson's and type II diabetes. There is an unmet need for synthetic agents that are able to mediate particular steps in the pathway between soluble proteins in their native unfolded state and their insoluble β-sheet rich aggregates. We have previously reported classes of α-helix mimetic that agonize or antagonize islet amyloid polypeptide aggregation, depending on the presence of a lipid bilayer. Here we investigate a novel mixed benzamide and pyridylamide scaffold that gives improved activity and explores the role of side-chain polarity, backbone rigidity and curvature in inhibiting lipid-catalyzed fibrillization.

Original language	English (US)
Article number	46004
Pages (from-to)	3670-3673
Number of pages	4
Journal	Tetrahedron Letters
Volume	56
Issue number	23
DOIs	https://doi.org/10.1016/j.tetlet.2015.02.132
State	Published - May 25 2015

Keywords

Amyloid β-peptides
Diabetes
Helical structures
Proteomimetics
α-Helix mimetics

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1016/j.tetlet.2015.02.132

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title = "Amphiphilic oligoamide α-helix peptidomimetics inhibit islet amyloid polypeptide aggregation",

abstract = "Abstract The abnormal deposition of proteins as insoluble plaques is associated with many diseases, including Alzheimer's, Parkinson's and type II diabetes. There is an unmet need for synthetic agents that are able to mediate particular steps in the pathway between soluble proteins in their native unfolded state and their insoluble β-sheet rich aggregates. We have previously reported classes of α-helix mimetic that agonize or antagonize islet amyloid polypeptide aggregation, depending on the presence of a lipid bilayer. Here we investigate a novel mixed benzamide and pyridylamide scaffold that gives improved activity and explores the role of side-chain polarity, backbone rigidity and curvature in inhibiting lipid-catalyzed fibrillization.",

keywords = "Amyloid β-peptides, Diabetes, Helical structures, Proteomimetics, α-Helix mimetics",

author = "Kulikov, {Oleg V.} and Sunil Kumar and Mazin Magzoub and Knipe, {Peter C.} and Ishu Saraogi and Sam Thompson and Miranker, {Andrew D.} and Hamilton, {Andrew D.}",

note = "Funding Information: We thank the University Of Oxford , the National Institutes of Health (NIH; GM094693 , CA67771 ) and the National Science Foundation (NSF; CHE-0750357 ) for their generous support of this work. Publisher Copyright: {\textcopyright} 2015 Published by Elsevier Ltd.",

year = "2015",

month = may,

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doi = "10.1016/j.tetlet.2015.02.132",

language = "English (US)",

volume = "56",

pages = "3670--3673",

journal = "Tetrahedron Letters",

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T1 - Amphiphilic oligoamide α-helix peptidomimetics inhibit islet amyloid polypeptide aggregation

AU - Kulikov, Oleg V.

AU - Kumar, Sunil

AU - Magzoub, Mazin

AU - Knipe, Peter C.

AU - Saraogi, Ishu

AU - Thompson, Sam

AU - Miranker, Andrew D.

AU - Hamilton, Andrew D.

N1 - Funding Information: We thank the University Of Oxford , the National Institutes of Health (NIH; GM094693 , CA67771 ) and the National Science Foundation (NSF; CHE-0750357 ) for their generous support of this work. Publisher Copyright: © 2015 Published by Elsevier Ltd.

PY - 2015/5/25

Y1 - 2015/5/25

N2 - Abstract The abnormal deposition of proteins as insoluble plaques is associated with many diseases, including Alzheimer's, Parkinson's and type II diabetes. There is an unmet need for synthetic agents that are able to mediate particular steps in the pathway between soluble proteins in their native unfolded state and their insoluble β-sheet rich aggregates. We have previously reported classes of α-helix mimetic that agonize or antagonize islet amyloid polypeptide aggregation, depending on the presence of a lipid bilayer. Here we investigate a novel mixed benzamide and pyridylamide scaffold that gives improved activity and explores the role of side-chain polarity, backbone rigidity and curvature in inhibiting lipid-catalyzed fibrillization.

AB - Abstract The abnormal deposition of proteins as insoluble plaques is associated with many diseases, including Alzheimer's, Parkinson's and type II diabetes. There is an unmet need for synthetic agents that are able to mediate particular steps in the pathway between soluble proteins in their native unfolded state and their insoluble β-sheet rich aggregates. We have previously reported classes of α-helix mimetic that agonize or antagonize islet amyloid polypeptide aggregation, depending on the presence of a lipid bilayer. Here we investigate a novel mixed benzamide and pyridylamide scaffold that gives improved activity and explores the role of side-chain polarity, backbone rigidity and curvature in inhibiting lipid-catalyzed fibrillization.

KW - Amyloid β-peptides

KW - Diabetes

KW - Helical structures

KW - Proteomimetics

KW - α-Helix mimetics

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M3 - Article

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JO - Tetrahedron Letters

JF - Tetrahedron Letters

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ER -

Amphiphilic oligoamide α-helix peptidomimetics inhibit islet amyloid polypeptide aggregation

Abstract

Keywords

ASJC Scopus subject areas

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