Nonpeptidic Alpha-Helix and Beta-Strand Mimetics

非肽 α 螺旋和 β 链模拟物

• 批准号: 0848410
• 负责人: Paramjit Arora
• 金额: $ 37.5万
• 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: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0848410&HistoricalAwards=false
• 关键词: Nonpeptidic; Alpha; Helix; Beta; Strand

With support from the Organic and Macromolecular Chemistry Program for this new award, Professor Paramjit Arora, of the Department of Chemistry at New York University, will provide synthetic mimics of protein subdomains that can modulate the function of chosen proteins. Targets include nonpeptidic oligomers that mimic alpha-helical and beta-strand conformations, contain chiral backbones, and display protein-like functionality. The beta-strand mimics are synthesized by replacing amide bonds in a peptide by triazole rings. The potential of these resulting triazolamers as inhibitors of specific proteases and protein-protein interactions will be evaluated. The principal investigator's group will also prepare nonpeptidic helix mimetics composed of oxopiperazine units. The oxopiperazine oligomers will be synthesized using standard procedures from natural and nonnatural amino acids. They will determine the solution and solid-state conformations of oligooxopiperizines and test their potential to inhibit protein-protein interactions. NMR spectroscopy in conjunction with molecular modeling will be used to elucidate structural features of these nonpeptidic oligomers that display protein-like functionality.With this award, Professor Arora will demonstrate chemical design principles and synthetic organic methods to prepare new classes of biologically active compounds. This approach will afford 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 principal investigator's research team include graduate and undergraduate students, including members of the underrepresented groups. The PI's research group is comprised of greater than 50% women and underrepresented minority students, including minority high school students from New York City high schools. The results of the proposed research will be disseminated through traditional and web-based methods. Students trained on the project will go on to careers in the pharmaceutical or biotechnology industry, or academia, and will thus contribute to the US scientific endeavor and the economy. Professor Arora 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 through New York University's Faculty Resource Network (FRN). The FRN is a faculty development initiative whose mission is to improve the quality of teaching and learning at its member and affiliate institutions, a consortium of 13 historically black colleges and universities in the South and 15 regional liberal arts colleges. Professor Arora's workshop introduces educators at these institutions to contemporary approaches in drug design, and highlights the fundamental role organic chemistry plays in understanding the complexity of biological systems.

在有机和大分子化学项目的支持下，纽约大学化学系的Paramjit Arora教授将提供蛋白质亚域的合成模拟物，这些模拟物可以调节选定蛋白质的功能。靶标包括模拟α -螺旋和β -链构象的非肽低聚物，包含手性骨架，并显示类似蛋白质的功能。β链模拟物是通过用三唑环取代肽中的酰胺键合成的。将评估这些所得的三唑胺作为特定蛋白酶和蛋白-蛋白相互作用抑制剂的潜力。主要研究者小组还将制备由氧哌嗪单位组成的非肽螺旋模拟物。奥哌嗪低聚物将使用标准程序从天然和非天然氨基酸合成。他们将确定低聚哌嗪的溶液和固态构象，并测试其抑制蛋白质-蛋白质相互作用的潜力。核磁共振波谱结合分子模型将用于阐明这些显示蛋白质样功能的非肽低聚物的结构特征。凭借该奖项，阿罗拉教授将展示化学设计原理和合成有机方法，以制备新型生物活性化合物。这种方法将提供仿生低聚物，有望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，提供了从氨基酸组装而成的非肽低聚物的途径，同时保留了手性主链和侧链的功能。从事这项工作的学生将在分子设计、构象分析、合成和生物化学方面获得广泛的经验。首席研究员的研究团队成员包括研究生和本科生，包括代表性不足的群体的成员。PI的研究小组由超过50%的女性和代表性不足的少数族裔学生组成，其中包括来自纽约市高中的少数族裔高中生。拟议的研究结果将通过传统的和基于网络的方法传播。参加该项目的学生将继续在制药或生物技术行业或学术界工作，从而为美国的科学事业和经济做出贡献。阿罗拉教授将继续通过纽约大学教师资源网络（FRN）组织研讨会，讨论化学和生物学界面的研究和教学进展，从而吸引在少数族裔机构任教的教育工作者。FRN是一项教师发展倡议，其使命是提高其成员和附属机构的教学质量，这是一个由南方13所历史悠久的黑人学院和大学以及15所地区性文理学院组成的联盟。阿罗拉教授的研讨会向这些机构的教育工作者介绍了药物设计的当代方法，并强调了有机化学在理解生物系统复杂性方面所起的基本作用。