A Systematic Approach to Targeting Protein Interfaces with Nonpeptidic Helix Mimetics

用非肽螺旋模拟物靶向蛋白质界面的系统方法

• 批准号: 1151554
• 负责人: Paramjit Arora
• 金额: $ 36万
• 依托单位: New York University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1151554&HistoricalAwards=false
• 关键词: Systematic; Approach; Targeting; Protein; Interfaces

With support from the Chemistry of Life Processes Program in the Chemistry Division of the National Science Foundation, Professors Paramjit Arora and Richard Bonneau, of the Departments of Chemistry and Biology at New York University, will study synthetic mimics of protein subdomains that can modulate the function of chosen proteins. Targets include nonpeptidic oligomers that mimic the alpha-helical conformation and display protein-like functionality. The oxopiperazine helix mimetic oligomers will be synthesized using standard procedures from natural and nonnatural amino acids. The researchers will develop experimental and computational approaches for screening libraries of nonpeptidic helix mimetics against model protein targets to identify high affinity, selective ligands. They will implement computational tools that can accurately predict local conformations of nonpeptidic oligomers and estimate optimum constructs for chosen protein receptors. Furthermore, they will explore the potential of oligooxopiperazines to target the DNA major groove. With this award, these researchers will demonstrate computational and synthetic design principles, and synthetic organic methods to develop new classes of biologically active compounds. This approach will result in biomimetic oligomers that are anticipated to become valuable reagents for the biomedical community. This work represents a new direction in bioorganic chemistry: providing access to nonpeptidic oligomers that assemble from amino acids while preserving the chiral backbone and side chain functionality. Students engaged in this work will gain broad experience in molecular design, conformational analysis, synthesis, and biochemistry. Members of the research team will include graduate and undergraduate students, drawing also from underrepresented groups. Students trained on the project may go on to careers in the pharmaceutical or biotechnology industry, or academia, and will thus contribute to the US scientific endeavor and the economy. Professors Arora and Bonneau will continue to engage educators that teach at predominantly minority institutions by organizing workshops that discuss research and teaching advances at the interface of chemistry and biology.

在国家科学基金会化学部生命过程化学项目的支持下，纽约大学化学和生物学系的Paramjit Arora和Richard Bonneau教授将研究蛋白质亚结构域的合成模拟物，这些蛋白质亚结构域可以调节所选蛋白质的功能。靶标包括模拟α-螺旋构象并显示蛋白质样功能的非肽寡聚体。氧代哌嗪螺旋模拟物低聚物将使用标准程序从天然和非天然氨基酸合成。研究人员将开发实验和计算方法，用于筛选针对模型蛋白质靶点的非肽螺旋模拟物文库，以识别高亲和力，选择性配体。他们将实施计算工具，可以准确地预测非肽寡聚体的局部构象，并估计所选蛋白质受体的最佳结构。此外，他们将探索寡氧哌嗪靶向DNA大沟的潜力。凭借该奖项，这些研究人员将展示计算和合成设计原理，以及开发新类别生物活性化合物的合成有机方法。这种方法将导致仿生低聚物，预计将成为生物医学界有价值的试剂。这项工作代表了生物有机化学的一个新方向：提供从氨基酸组装的非肽低聚物，同时保留手性骨架和侧链功能。从事这项工作的学生将获得分子设计，构象分析，合成和生物化学方面的广泛经验。研究小组的成员将包括研究生和本科生，也来自代表性不足的群体。在该项目上接受培训的学生可以继续从事制药或生物技术行业或学术界的职业，从而为美国的科学奋进和经济做出贡献。教授阿罗拉和博诺将继续从事教育工作者，在主要少数民族机构通过组织研讨会，讨论在化学和生物学的接口研究和教学进展任教。