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Foldamers: Novel Ligands for Diverse Protein Surfaces

Foldamers：用于多种蛋白质表面的新型配体

基本信息

批准号：
8536825
负责人：
Alanna Schepartz
金额：
$ 32.6万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8536825
关键词：
Adverse effects Agonist Amyloid beta-Protein Antidiabetic Drugs Area Arginine Biological CCR5 gene CXCR4 gene Cell Nucleus Cell membrane Cell surface Cells Clinical Complement Cytosol Disease Drug Industry Drug Targeting Engineering Ensure Extracellular Domain Funding G Protein-Coupled Receptor Genes Goals Half-Life Health Human Immune Life Ligands Locales Malignant Neoplasms Mammalian Cell Medicine Membrane Proteins Methods Modeling Non-Insulin-Dependent Diabetes Mellitus Osteoporosis Pathway interactions Penetration Peptides Permeability Pharmaceutical Preparations Property Proteins Reporting Request for Applications Research Roche brand of trastuzumab Signal Transduction Structure Structure-Activity Relationship System Therapeutic Time Tissues Variant Work chemokine receptor combinatorial cost design extracellular glucagon-like peptide 1 improved inhibitor/antagonist interest novel peptide analog peptide structure protein aminoacid sequence protein protein interaction receptor research study therapeutic protein trafficking uptake

项目摘要

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.

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。