Biomolecular Recognition with Artificial Alpha Helices

人工阿尔法螺旋的生物分子识别

• 批准号: 7373495
• 负责人: Paramjit S Arora
• 金额: $ 21.79万
• 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/7373495
• 关键词: Acids; Affinity; Amino Acids; Binding; Biological; Biological Preservation; Buffers; Carbohydrates; Carbon; Cell physiology; Class; Code; Complex; DNA; DNA Binding; Development; Elements; Endoribonucleases; Evaluation; Face; Funding; Gene Expression; HIV-1; Helix (Snails); Hydrogen Bonding; Length; Major Groove; Methods; Modeling; Molecular; Molecular Biology; Molecular Conformation; Nucleic Acids; Object Attachment; Pancreatic ribonuclease; Peptides; Placement; Play; Preparation; Proteins; Research; Research Personnel; Ribonucleases; Role; Side; Solvents; Standards of Weights and Measures; Study models; Surface; System; Zinc Fingers; alpha helix; aqueous; base; covalent bond; crosslink; design; drug development; ear helix; mimetics; molecular recognition; novel strategies; programs; protein folding; protein protein interaction; protein structure; receptor; tool

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）：细胞功能依赖于生物分子（蛋白质、RNA、DMA和碳水化合物）之间高度特异性的相互作用。α -螺旋是蛋白质结构中无处不在的元素，在许多这些相互作用中起着重要作用。α -螺旋模拟物可以预见地破坏这些相互作用，这将是分子生物学中宝贵的工具，也是药物开发的潜在线索。现有的螺旋稳定方法的一个局限性是，它们牺牲了侧链的功能，以产生交联和成核螺旋构象。修改侧链使它们无法被分子识别，并且至少阻断了假定的螺旋的一个面。我们已经成功地创造了一种合成短稳定α螺旋的一般方法，这种方法允许严格保存螺旋表面。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。交联的内部位置使得利用完整的螺旋功能进行分子识别成为可能。在初步研究中，我们已经证明了这种新方法可以产生异常稳定的人工α螺旋。在这个应用中，我们探索了这些人工螺旋在识别特定蛋白质口袋和DNA主要凹槽方面的效用。