Foldamers: Novel Ligands for Diverse Protein Surfaces

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。

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.