Foldamers: Novel Ligands for Diverse Protein Surfaces

Foldamers：用于多种蛋白质表面的新型配体

• 批准号: 7739370
• 负责人: Alanna Schepartz
• 金额: $ 33.08万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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/7739370
• 关键词: Acquired Immunodeficiency Syndrome; Adverse effects; Agonist; Antidiabetic Drugs; Area; Arginine; Biological; CCR5 gene; CXCR4 gene; Cell Nucleus; Cell membrane; Cell surface; Cells; Clinical; Complement; Cytosol; Disease; Drug Delivery Systems; Drug Industry; ERBB2 gene; Engineering; Ensure; Extracellular Domain; Funding; G Protein-Coupled Receptor Genes; GLP-I receptor; Goals; Guidelines; Half-Life; Health; Human; Immune; Kinetics; Life; Ligands; Locales; Malignant Neoplasms; Mammalian Cell; Medicine; Membrane; Membrane Proteins; Metal Ion Binding; Methods; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Penetration; Peptides; Permeability; Pharmaceutical Preparations; Property; Proteins; Reporting; Request for Applications; Research; Roche brand of trastuzumab; Side; Signal Transduction; Structure; Structure-Activity Relationship; System; TP53 gene; Therapeutic; Thermodynamics; Time; Tissues; Variant; Work; catalyst; chemokine receptor; combinatorial; cost; design; extracellular; frontier; improved; inhibitor/antagonist; interest; novel; peptide analog; peptide structure; protein aminoacid sequence; protein protein interaction; public health relevance; receptor; research study; therapeutic protein; trafficking; uptake

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.

该申请请求支持以继续我们对 β 肽结构的探索 生物学功能。我们在此建立在两个最令人兴奋和最具影响力的发现的基础上 第一个融资周期的：(1) 精心设计的 β 肽有效地模仿 ¿ 螺旋并作为蛋白质相互作用抑制剂，其特性很容易 通过组合方法改进； (2) β-肽可以被设计来穿越 质膜并保留细胞质中的生物功能，无需添加 一个大的“八精氨酸”标签，促进其应用于细胞内靶标。因此， 该应用程序的具体目标是首先（目标 1）摆脱“证明- 原则”目标，并为两个经过充分验证的药物目标设计β-肽配体 可以受益于 β 肽所体现的独特特性组合： GLP-1 受体 (GLP-1R)，抗糖尿病药物 Byetta 的靶标，以及 ErbB2 受体，单克隆抗体赫赛汀的靶点”。我们还描述了可以抑制 或从质膜内激活 CXCR4 和 CCR5 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-肽是扩大其细胞质适用性的第一步 目标。 β-肽不受蛋白水解降解的事实使得它们 独特地能够报告肽实现摄取的多种途径 一旦他们这样做了，细胞内的交通就会发生变化。