Foldamers: Novel Ligands for Diverse Protein Surfaces
Foldamers: Novel Ligands for Diverse Protein Surfaces
批准号:
8536825
负责人:
Alanna Schepartz
金额:
$32.6万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2005
资助国家:
美国
项目状态:
已结题
起止时间:
2005-08-01 至 2014-07-31
关键词:
Adverse effectsAgonistAmyloid beta-ProteinAntidiabetic DrugsAreaArginineBiologicalCCR5 geneCXCR4 geneCell NucleusCell membraneCell surfaceCellsClinicalComplementCytosolDiseaseDrug IndustryDrug TargetingEngineeringEnsureExtracellular DomainFundingG Protein-Coupled Receptor GenesGoalsHalf-LifeHealthHumanImmuneLifeLigandsLocalesMalignant NeoplasmsMammalian CellMedicineMembrane ProteinsMethodsModelingNon-Insulin-Dependent Diabetes MellitusOsteoporosisPathway interactionsPenetrationPeptidesPermeabilityPharmaceutical PreparationsPropertyProteinsReportingRequest for ApplicationsResearchRoche brand of trastuzumabSignal TransductionStructureStructure-Activity RelationshipSystemTherapeuticTimeTissuesVariantWorkchemokine receptorcombinatorialcostdesignextracellularglucagon-like peptide 1improvedinhibitor/antagonistinterestnovelpeptide analogpeptide structureprotein aminoacid sequenceprotein protein interactionreceptorresearch studytherapeutic proteintraffickinguptake
中文摘要
该应用程序请求支持,以继续探索β-肽结构,
生物功能。我们在此建立在两个最令人兴奋和最具影响力的发现之上
第一个资金周期:(1)精心设计的β肽有效地模仿了
螺旋和功能作为蛋白质相互作用抑制剂,具有易于
通过组合方法改进;和(2)β-肽可以被工程化以穿过
细胞膜和保留生物功能的细胞质,而不添加
一个大的“八精氨酸”标签,促进其应用于细胞内的目标。因此
本申请的具体目的是首先(目的1)远离“证明”,
原则”的目标,并为两个经过充分验证的药物靶点设计β-肽配体,
可以受益于β-肽所体现的特性的独特组合:
GLP-1受体(GLP-1 R),抗糖尿病药物Byetta的靶点,以及ErbB 2
受体,mAb赫赛汀的靶标”。我们还描述了β-肽,
或从质膜内激活CXCR 4和CCR 5趋化因子受体。
在目标2中,我们描述了系统优化和利用细胞的实验,
渗透性β-肽作为扩大其对细胞溶质的适用性的第一步
目标的事实上,β-肽对蛋白水解降解具有免疫力,
独特地能够报告肽实现摄取的无数途径
和细胞内的交通。
英文摘要
This application requests support to continue our exploration of beta-peptide structure and
biologic function. We build herein on two of the most exciting and impacting discoveries
of the first funding cycle: (1) that carefully designed beta-peptides effectively mimic ¿-
helices and function as protein interaction inhibitors, with properties that are easily
improved by combinatorial methods; and (2) that beta-peptides can be engineered to traverse
the plasma membrane and retain biologic function in the cytosol, without the addition of
a large "octa-arginine" tag, facilitating their application to intracellular targets. Thus, the
Specific Aims of this application are to first (Aim 1) move away from "proof-of-
principle" targets, and design beta-peptide ligands for two well-validated drug targets that
could benefit from the unique combination of properties embodied by a beta-peptide: the
GLP-1 receptor (GLP-1R), a target of the antidiabetes drug Byetta", and the ErbB2
receptor, a target of the mAb Herceptin". We also describe beta-peptides that either inhibit
or activate CXCR4 and CCR5 chemokine receptors from within the plasma membrane.
In Aim 2, we described experiments to systematically optimize and exploit cell-
permeable beta-peptides as a first step toward broadening their applicability to cytosolic
targets. The fact that beta-peptides are immune to proteolytic degradation makes them
uniquely capable of reporting on the myriad pathways by which peptides achieve uptake
and traffic within the cell once they do.
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DOI:
10.1021/ja510391n
发表时间:
2015-02-25
期刊:
Journal of the American Chemical Society
影响因子:
15
作者:
[LaRochelle JR, Cobb GB, Steinauer A, Rhoades E, Schepartz A]
通讯作者:
Schepartz A
DOI:
10.1021/ja508872q
发表时间:
2014-10-22
期刊:
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子:
15
作者:
[Miller, Jonathan P., Melicher, Michael S., Schepartz, Alanna]
通讯作者:
Schepartz, Alanna
DOI:
10.1021/ja910715u
发表时间:
2010-03-10
期刊:
Journal of the American Chemical Society
影响因子:
15
作者:
[Bautista AD, Appelbaum JS, Craig CJ, Michel J, Schepartz A]
通讯作者:
Schepartz A
DOI:
10.1002/ijch.201300063
发表时间:
2013-08
期刊:
ISRAEL JOURNAL OF CHEMISTRY
影响因子:
3.2
作者:
[Hobert, Elissa M., Doerner, Amy E., Walker, Allison S., Schepartz, Alanna]
通讯作者:
Schepartz, Alanna
DOI:
10.1016/j.chembiol.2012.05.022
发表时间:
2012-07-27
期刊:
Chemistry & biology
影响因子:
--
作者:
[Appelbaum JS, LaRochelle JR, Smith BA, Balkin DM, Holub JM, Schepartz A]
通讯作者:
Schepartz A
共 9 条
Fluorescence tools that illuminate biology and inspire translation
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批准号:10372854
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项目类别:
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资助金额:$12.73万
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财政年份:2020
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依托单位:
Fluorescence tools that illuminate biology and inspire translation
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批准号:10365915
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Fluorescence tools that illuminate biology and inspire translation
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Repurposing the Ribosome for Exotic Polymers
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依托单位:
Repurposing the Ribosome for Exotic Polymers
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批准号:9999711
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项目类别:
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资助金额:$6.67万
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依托单位:
Directing the Mediator Complex: Bivalent approaches to Reconstituting or Inhibiti
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资助金额:$13.19万
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财政年份:2012
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负责人:Alanna Schepartz
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依托单位:
Foldamers: Novel Ligands for Diverse Protein Surfaces
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批准号:7928434
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项目类别:
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资助金额:$18.89万
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财政年份:2009
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负责人:Alanna Schepartz
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依托单位:
Small Molecule Tools to Image and Understand Sophisticated Protein Function
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批准号:9276914
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项目类别:
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资助金额:$18.98万
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财政年份:2008
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负责人:Alanna Schepartz
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依托单位:
Surveying protein partnerships and assembly with bipartite tetracysteine display
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批准号:7618748
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项目类别:
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资助金额:$28.0万
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财政年份:2008
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依托单位:
Surveying protein partnerships and assembly with bipartite tetracysteine display
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项目类别:
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资助金额:$26.78万
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财政年份:2008
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依托单位:
Small Molecule Tools to Image Sophisticated Protein Function
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批准号:8243508
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项目类别:
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资助金额:$31.25万
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财政年份:2008
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负责人:Alanna Schepartz
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依托单位:
Small Molecule Tools to Image Sophisticated Protein Function
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资助金额:$30.15万
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财政年份:2008
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Small Molecule Tools to Image Sophisticated Protein Function
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资助金额:$28.86万
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财政年份:2008
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Small Molecule Tools to Image and Understand Sophisticated Protein Function
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资助金额:$29.8万
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依托单位:
STRUCTURE OF HEXAMERIC BUNDLES OF BETA-AMINO ACID PEPTIDE U1F
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资助金额:$1.36万
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财政年份:2006
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负责人:Alanna Schepartz
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依托单位:
Foldamers: Novel Ligands for Diverse Protein Surfaces
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批准号:7270020
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资助金额:$41.77万
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国内基金
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Agonist-GPR119-Gs复合物的结构生物学研究
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