Nonpeptidic Alpha-Helix and Beta-Strand Mimetics

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-螺旋和β-链构象、含有手性骨架并显示蛋白质样功能的非肽寡聚体。 通过用三唑环取代肽中的酰胺键来合成β链模拟物。 将评价这些所得三唑啉作为特异性蛋白酶和蛋白质-蛋白质相互作用的抑制剂的潜力。 主要研究者小组还将制备由氧代哌嗪单元组成的非肽螺旋模拟物。 氧代哌嗪低聚物将使用标准程序从天然和非天然氨基酸合成。 他们将确定寡氧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。 NMR光谱结合分子建模将用于阐明这些非肽低聚物的结构特征，显示蛋白质样的功能。与此奖项，阿罗拉教授将展示化学设计原理和合成有机方法，以制备新的生物活性化合物类。 这种方法将提供仿生低聚物，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，提供了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。 主要研究者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%的妇女和代表性不足的少数民族学生组成，包括来自纽约市高中的少数民族高中生。 拟议研究的结果将通过传统方法和网络方法传播。 在该项目上接受培训的学生将继续在制药或生物技术行业或学术界的职业生涯，从而为美国的科学奋进和经济做出贡献。 阿罗拉教授将继续通过纽约大学教师资源网组织讲习班，讨论化学和生物学交叉领域的研究和教学进展，从而与在以少数族裔为主的机构任教的教育工作者接触。 FRN是一个教师发展倡议，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所区域文科学院组成的联盟。 Arora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的基本作用。

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.