Foldamers: Novel Ligands for Diverse Protein Surfaces

描述（由申请人提供）：本申请请求支持，以继续我们的探索？-肽的结构和生物学功能。我们在此建立在第一个融资周期中三个最令人兴奋和最具影响力的发现上：（1）精心设计的？肽有效地模仿？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的性质;（2）？-肽可以被工程化以穿过质膜并在胞质溶胶中保留生物学功能，而无需添加大的“八精氨酸”标签，从而促进其应用于细胞内靶点;以及（3）某些？多肽可以自发地自我组装成许多类似蛋白质的束，为它们用作催化剂铺平了道路。因此，本申请的具体目标是首先（目标1）远离“原理证明”目标，并设计？肽配体的两个经过充分验证的药物靶点，可以受益于独特的组合所体现的性质？肽：GLP-1受体（GLP-1 R），抗糖尿病药物ByettaTM的靶点，以及ErbB 2受体，mAb HerceptinTM的靶点。我们还描述了？抑制或激活质膜内CXCR 4和CCR 5趋化因子受体的肽。在目标2中，我们描述了系统优化和利用细胞渗透性？肽作为扩大其对细胞质靶点适用性的第一步。事实上，肽对蛋白水解降解免疫，这使得它们能够独特地报道肽一旦在细胞内被摄取和运输所通过的无数途径。最后，在目标3中，我们描述了两种方法，具有功能的肽束。在目标3.1中，我们描述了？- 含有氟化侧链的肽代替？hLeu，设计用于引导膜中的束组装。我们认为这一目标是特别令人兴奋的，因为在膜中选择性组装的蛋白质界面的设计代表了分子设计中的一个巨大的和目前未满足的挑战。在目标3.2中，我们描述了两种互补的方法，结合金属离子的肽束，这是设计？肽催化剂我们相信，这项应用中的实验将拓展蛋白质设计的前沿，并为构建？具有日益复杂的生物学功能的肽和束。公共卫生相关性：细胞表面或胞质溶胶中的蛋白质-蛋白质相互作用在人类医学中严重开发不足。?-肽作为这些相互作用的抑制剂具有独特的优点。该提案在2型糖尿病、癌症和艾滋病等多种疾病的背景下探讨了这些优势。

DESCRIPTION (provided by applicant): This application requests support to continue our exploration of ?-peptide structure and biologic function. We build herein on the three most exciting and impacting discoveries of the first funding cycle: (1) that carefully designed ?-peptides effectively mimic ?-helices and function as protein interaction inhibitors, with properties that are easily improved by combinatorial methods; (2) that ?-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; and (3) that certain ?-peptides self-assemble spontaneously into bundles that resemble proteins in many ways, paving the way for their use as catalysts. Thus, the Specific Aims of this application are to first (Aim 1) move away from "proof-of-principle" targets, and design ?-peptide ligands for two well-validated drug targets that could benefit from the unique combination of properties embodied by a ?-peptide: the GLP-1 receptor (GLP-1R), a target of the antidiabetes drug ByettaTM, and the ErbB2 receptor, a target of the mAb HerceptinTM. We also describe ?-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 ?-peptides as a first step toward broadening their applicability to cytosolic targets. The fact that ?-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. Finally in Aim 3 we describe two approaches to ?-peptide bundles with function. In Aim 3.1, we describe ? -peptides containing fluorinated side chains in place of ?hLeu, designed to guide bundle assembly in a membrane. We view this goal as particularly exciting, as the design of protein interfaces that assemble selectively in a membrane represents a formidable and currently unmet challenge in molecular design. In Aim 3.2, we describe two complementary approaches to ?-peptide bundles that bind metal ions, the essential first step in the design of ?-peptide catalysts. We believe that the experiments in this application will expand the frontiers of protein design and define guidelines for the construction of ?-peptides and bundles with increasingly sophisticated biologic function. PUBLIC HEALTH RELEVANCE: Protein-protein interactions on the cell surface or in the cytosol are grossly underexploited in human medicine. ?-peptides possess unique advantages as inhibitors of these interactions. This proposal explores these advantages in the context of diseases as diverse as type 2 diabetes, cancer, and AIDS.