Foldamers: Novel Ligands for Diverse Protein Surfaces

此应用程序请求支持以继续我们对β-肽结构和 生物功能。我们在这里建立在两个最令人兴奋和影响最大的发现之上 第一个资金周期：(1)精心设计的β-多肽有效地模拟- 螺旋和作为蛋白质相互作用抑制剂的功能，其特性很容易 通过组合方法进行改进；以及(2)β-肽可以被改造成穿越 质膜，并在胞浆中保留生物功能，而不添加 一个大的“八精氨酸”标签，便于将其应用于细胞内靶标。因此， 这个应用程序的具体目标是首先(目标1)从“证明-- 原则“靶点，并为两个经过充分验证的药物靶点设计β-肽配体 可以受益于由β-肽所体现的独特的特性组合： GLP-1受体(GLP-1R)，抗糖尿病药物Byetta“的靶标，以及ErbB2 受体，单抗Herceptin的靶标。我们还描述了抑制 或从质膜内激活CXCR4和CCR5趋化因子受体。 在目标2中，我们描述了系统地优化和开发细胞- 通透性β-肽作为扩大其在胞浆中应用的第一步 目标。事实上，β-肽对蛋白质降解具有免疫力，这使得它们 独一无二地能够报道多肽获得摄取的无数途径 一旦他们这样做了，小区内的流量。

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.