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: 7103421
• 负责人: Alanna Schepartz
• 金额: $ 41.76万
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7103421
• 关键词: Coronaviridae; HIV envelope protein; drug design /synthesis /production; glycoproteins; hydropathy; ligands; method development; nuclear magnetic resonance spectroscopy; p53 gene /protein; peptide chemical synthesis; peptide library; protein binding; protein protein interaction; protein structure function; respiratory syncytial virus; severe acute respiratory syndrome; virus envelope; virus protein

DESCRIPTION (provided by applicant): This application builds on a foundation of recent results from our laboratory detailing a general strategy for the design of beta-peptides that are highly 14-helical in water and bind with high affinity to protein surfaces, such as the p53AD interaction domain of hDM2. In Aim 1 we explore the structural features that contribute to 14-helix stability in water and the ability of the 14-helical beta-peptide beta53-1 to recognize protein surfaces. We will complete an extensive "host-guest" analysis that will classify all proteinogenic and selected non-proteinogenic side chains as 14-helix stabilizing, destabilizing, or neutral, generating a database of position-dependent, 14-helix propensities in water; determine the NMR solution structure of beta53-1 to support the host-guest data and guide future design efforts; and explore whether the stability or affinity of beta53-1 can be improved by introduction of cyclic ACHC residues. In Aim 2 we build on the results of Aim 1 to design beta-peptide ligands for the envelope glycoproteins of 3 viruses that threaten human health, national security, or both: HIV, human respiratory syncytial virus (HRSV), and the coronavirus that causes severe acute respiratory syndrome (SARS-CoV). The experiments in Aim 2 will validate our betapeptide design strategy in a system that is highly relevant and tractable, and will likely provide leads for future drug development. In Aim 3 we develop methods to synthesize, analyze, and screen beta-peptide combinatorial libraries, and use them to optimize the affinities (and minimize the size) of beta-peptides identified in Aims 1 and 2. This aim also includes an experiment to identify cell-permeable beta53-1 library members, information that will guide design of beta-peptide ligands for additional validated targets. Taken together, the experiments in this application will provide fundamental information on ligand design and help achieve 1 of the most central and critical (yet unmet) goals of chemical biology research, the rapid identification of high affinity ligands for the vast array of potential non-enzymatic protein targets.

描述（由申请人提供）：本申请建立在我们实验室最新结果的基础上，详细介绍了设计 β 肽的一般策略，该肽在水中呈高度 14 螺旋，并以高亲和力与蛋白质表面（例如 hDM2 的 p53AD 相互作用结构域）结合。在目标 1 中，我们探索了有助于 14 螺旋在水中稳定性的结构特征以及 14 螺旋 β 肽 beta53-1 识别蛋白质表面的能力。我们将完成广泛的“主客体”分析，将所有蛋白质侧链和选定的非蛋白质侧链分类为 14 螺旋稳定、不稳定或中性，生成水中位置依赖性 14 螺旋倾向的数据库；确定beta53-1的NMR解决方案结构以支持主客体数据并指导未来的设计工作；并探讨是否可以通过引入环状ACHC残基来提高β53-1的稳定性或亲和力。在目标 2 中，我们以目标 1 的结果为基础，为威胁人类健康和/或国家安全的 3 种病毒的包膜糖蛋白设计 β 肽配体：HIV、人类呼吸道合胞病毒 (HRSV) 和引起严重急性呼吸综合征的冠状病毒 (SARS-CoV)。目标 2 中的实验将在高度相关且易于处理的系统中验证我们的 β 肽设计策略，并可能为未来的药物开发提供线索。在目标 3 中，我们开发了合成、分析和筛选 β 肽组合文库的方法，并使用它们来优化目标 1 和 2 中鉴定的 β 肽的亲和力（并最小化大小）。该目标还包括鉴定细胞可渗透的 beta53-1 文库成员的实验，这些信息将指导其他经过验证的靶点的 β 肽配体的设计。总而言之，本应用中的实验将提供配体设计的基本信息，并有助于实现化学生物学研究最核心和最关键（但尚未实现）的目标之一，即快速识别大量潜在非酶蛋白靶标的高亲和力配体。