Biomolecular Recognition with Artificial Alpha Helices

人工阿尔法螺旋的生物分子识别

• 批准号: 7122163
• 负责人: Paramjit S Arora
• 金额: $ 0.5万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7122163
• 关键词: DNA binding protein; biomimetics; chemical models; chemical stability; chemical synthesis; conformation; covalent bond; hydrogen bond; molecular shape; pancreatic ribonuclease; protein binding; protein protein interaction; protein structure; synthetic peptide

DESCRIPTION (provided by applicant): Cellular function depends on highly specific interactions between biomolecules {proteins, RNA, DMA, and carbohydrates). Alpha-helices, ubiquitous elements of protein structures, play fundamental roles in many of these interactions. Alpha-helix mimetics that can predictably disrupt these interactions would be invaluable tools in molecular biology, and potential leads in drug development. A limitation of existing methods for helix stabilization is that they sacrifice side chain functionality to create crosslinks and nucleate helical conformations. Modifying side chains makes them unavailable for molecular recognition and blocks at least one face of the putative helix. We have succeeded in creating a general approach for the synthesis of short stable alpha helices that allows strict preservation of the helix surfaces. Our strategy involves replacement of one of the main chain hydrogen bonds in the target alpha-helix with a covalent bond. The internal placement of the crosslink makes it possible to take advantage of the full helix functionality for molecular recognition. In preliminary studies, we have demonstrated that this new method results in unusually stable artificial alpha-helices. In this application, we explore the utility of these artificial helices for recognition of specific protein pockets and DNA major grooves. With regards to specific aims, (1) we will determine whether replacement of a main chain hydrogen bond in a putative helix with a carbon-carbon bond continually results in highly stable and helical peptides. (2) We will prepare artificial helices that target model (RNase S and GCN4) and therapeutically important protein-protein interactions (HIV-1 gp41) to assess the biological efficacy of these compounds. (3) We will initiate research efforts to develop a new class of sequence-specific DNA binding molecules. Combined these three aims will validate a new approach for the preparation of artificial alpha-helices and their potential use in biomolecular recognition.

描述（由申请人提供）：细胞功能取决于生物分子（蛋白质、RNA、DMA和碳水化合物）之间的高度特异性相互作用。α-螺旋是蛋白质结构中普遍存在的元素，在许多这些相互作用中发挥着重要作用。可以预见地破坏这些相互作用的α-螺旋模拟物将是分子生物学中的宝贵工具，也是药物开发的潜在领导者。用于螺旋稳定化的现有方法的局限性在于它们牺牲侧链官能度以产生交联并使螺旋构象成核。修饰侧链使它们无法用于分子识别，并阻断推定螺旋的至少一个面。我们已经成功地创建了一个通用的方法，用于合成短的稳定的α螺旋，允许严格保存的螺旋表面。我们的策略包括用共价键取代目标α-螺旋中的一个主链氢键。交联的内部放置使得可以利用完整的螺旋功能进行分子识别。在初步研究中，我们已经证明这种新方法可以产生异常稳定的人工α螺旋。在这个应用程序中，我们探索这些人工螺旋识别特定的蛋白质口袋和DNA大沟的效用。 关于具体的目标，（1）我们将确定在假定的螺旋中用碳-碳键取代主链氢键是否会持续导致高度稳定的螺旋肽。(2)我们将制备靶向模型（RNase S和GCN 4）和治疗上重要的蛋白质-蛋白质相互作用（HIV-1 gp 41）的人工螺旋，以评估这些化合物的生物学功效。(3)我们将开展研究工作，开发一类新的序列特异性DNA结合分子。结合这三个目标将验证一种新的方法来制备人工α-螺旋及其在生物分子识别中的潜在用途。