Mimicry of Amyloid Oligomers
Mimicry of Amyloid Oligomers
批准号:
9205515
负责人:
JAMES S NOWICK
金额:
$29.14万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-02-01 至 2020-01-31
关键词:
Alzheimer&aposs DiseaseAmino AcidsAmyloidAmyloid beta-ProteinAmyloidosisBiologicalBiological ModelsC-terminalChemical ModelsDiseaseGoalsKnowledgeLeadMeasuresMolecularMutationNeurodegenerative DisordersParkinson DiseasePeptidesPharmaceutical PreparationsPhasePrion DiseasesPropertyProteinsResolutionRoentgen RaysStructureTailThermodynamicsabeta oligomeramyloid peptidebeta pleated sheetbiophysical analysisbiophysical propertiescrosslinkcytotoxicitydesignmimicrynovel therapeuticspolypeptideprevent
中文摘要
项目摘要/摘要:淀粉样蛋白低聚物的模拟
英文摘要
Project Summary/Abstract: Mimicry of Amyloid Oligomers
Amyloid oligomers now thought to be the damaging molecular species in Alzheimer's disease, Parkinson's
disease, and many other amyloid diseases. Understanding the structures of these oligomers is essential to
understanding their mechanism of action, and quite possibly to developing drugs to prevent or treat these
diseases. Studying the structures of the oligomers at high resolution is challenging, because the oligomers are
heterogeneous and dynamic, forming a variety of sizes and structures that can interconvert. The oligomers are
metastable, with fibrils being the more thermodynamically stable species. Only a few studies have provided
glimpses of amyloid oligomers at atomic resolution. Thus far, the there are no atomic-resolution structures of
oligomers of the beta-amyloid peptide, Abeta, the 40 or 42 amino acid polypeptide closely associated with
Alzheimer's disease.
This proposal aims to determine the structures of oligomers formed by Abeta by incorporating key
fragments of Abeta into macrocyclic beta-sheet peptides designed to mimic the key beta-hairpin building
blocks that are thought to make up Abeta oligomers. The PI has determined X-ray crystallographic structures
at atomic resolution of trimers formed macrocyclic beta-sheet peptides containing fragments from the central
and the C-terminal regions of Abeta. The trimers have a hitherto unprecedented structure consisting of a
triangular arrangement of beta-hairpins that pack together at the three vertices. The trimers further assemble to
form hexamers and dodecamers.
This proposal aims to build on the discovery of these trimers and higher-order oligomeric assemblies. The
broad overarching goal is to understand the relationship between the atomic-resolution structures of the
oligomers and their biological and biophysical properties. To achieve these goals, the PI will synthesize
macrocyclic beta-sheet peptides that incorporate different aspects of Abeta structure, determine the X-ray
crystallographic structures of the oligomers that these peptides form, measure their cytotoxicity, elucidate their
mechanisms of cytotoxcity, and correlate their cytotoxicity and their crystallographic structure by means of
biophysical studies of their solution-phase properties.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Synthesis and Evaluation of aza-Novo29 as an Antibiotic Candidate
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批准号:10527638
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项目类别:
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资助金额:$21.71万
-
财政年份:2022
-
负责人:JAMES S NOWICK
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依托单位:
Synthesis and Evaluation of aza-Novo29 as an Antibiotic Candidate
-
批准号:10624354
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项目类别:
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资助金额:$18.34万
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财政年份:2022
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负责人:JAMES S NOWICK
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依托单位:
Structural and Biological Characterization of Diverse Oligomers Derived from Abeta
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批准号:10214205
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项目类别:
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资助金额:$137.31万
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财政年份:2021
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负责人:JAMES S NOWICK
-
依托单位:
Amyloidogenic Antibiotics
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批准号:10306399
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项目类别:
-
资助金额:$18.49万
-
财政年份:2020
-
负责人:JAMES S NOWICK
-
依托单位:
Synthesis and Studies of a New Family of Antibiotics
-
批准号:9231356
-
项目类别:
-
资助金额:$17.35万
-
财政年份:2016
-
负责人:JAMES S NOWICK
-
依托单位:
Synthesis and Studies of a New Family of Antibiotics
-
批准号:9014830
-
项目类别:
-
资助金额:$19.85万
-
财政年份:2016
-
负责人:JAMES S NOWICK
-
依托单位:
Mimicry of Amyloid Oligomers
-
批准号:8607967
-
项目类别:
-
资助金额:$28.89万
-
财政年份:2012
-
负责人:JAMES S NOWICK
-
依托单位:
Mimicry of Amyloid Oligomers
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批准号:8413852
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项目类别:
-
资助金额:$28.13万
-
财政年份:2012
-
负责人:JAMES S NOWICK
-
依托单位:
Mimicry of Amyloid Oligomers
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批准号:8239411
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项目类别:
-
资助金额:$27.7万
-
财政年份:2012
-
负责人:JAMES S NOWICK
-
依托单位:
Chemical Models of Protein beta-Sheet Interactions
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批准号:7847773
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项目类别:
-
资助金额:$9.82万
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财政年份:2009
-
负责人:JAMES S NOWICK
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依托单位:
NEW STRATAGIES FOR FORMATION OF PEPTIDE BETA-SHEETS
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批准号:2186610
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项目类别:
-
资助金额:$9.37万
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财政年份:1994
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负责人:JAMES S NOWICK
-
依托单位:
CHEMICAL MODELS OF PROTEIN BETA SHEET INTERACTIONS
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批准号:6385799
-
项目类别:
-
资助金额:$19.18万
-
财政年份:1994
-
负责人:JAMES S NOWICK
-
依托单位:
CHEMICAL MODELS OF PROTEIN BETA SHEET INTERACTIONS
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批准号:2851757
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项目类别:
-
资助金额:$23.0万
-
财政年份:1994
-
负责人:JAMES S NOWICK
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依托单位:
CHEMICAL MODELS OF PROTEIN BETA SHEET INTERACTIONS
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批准号:6310712
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项目类别:
-
资助金额:$1.87万
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财政年份:1994
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负责人:JAMES S NOWICK
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依托单位:
Chemical Models of Protein beta-Sheet Interactions
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批准号:6873241
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项目类别:
-
资助金额:$28.59万
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财政年份:1994
-
负责人:JAMES S NOWICK
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依托单位:
Chemical Models of Protein beta-Sheet Interactions
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批准号:6987174
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项目类别:
-
资助金额:$26.29万
-
财政年份:1994
-
负责人:JAMES S NOWICK
-
依托单位:
Chemical Models of Protein beta-Sheet Interactions
-
批准号:7163421
-
项目类别:
-
资助金额:$25.4万
-
财政年份:1994
-
负责人:JAMES S NOWICK
-
依托单位:
NEW STRATEGIES FOR FORMATION OF PEPTIDE BETA-SHEETS
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批准号:2186611
-
项目类别:
-
资助金额:$10.03万
-
财政年份:1994
-
负责人:JAMES S NOWICK
-
依托单位:
NEW STRATAGIES FOR FORMATION OF PEPTIDE BETA-SHEETS
-
批准号:2186609
-
项目类别:
-
资助金额:$9.17万
-
财政年份:1994
-
负责人:JAMES S NOWICK
-
依托单位:
CHEMICAL MODELS OF PROTEIN BETA SHEET INTERACTIONS
-
批准号:6519526
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项目类别:
-
资助金额:$19.67万
-
财政年份:1994
-
负责人:JAMES S NOWICK
-
依托单位:
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