A Systematic Approach to Targeting Protein Interfaces with Nonpeptidic Helix Mimetics

在美国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系的帕罗吉特·阿罗拉教授和理查德·博诺教授将研究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。靶标包括模仿α-螺旋构象并显示蛋白质样功能的非肽低聚物。将使用标准程序从天然和非天然氨基酸中合成奥哌嗪螺旋模拟低聚物。研究人员将开发实验和计算方法，根据模型蛋白质靶标筛选非肽螺旋模拟物文库，以确定高亲和力、选择性配体。他们将实施计算工具，可以准确预测非肽低聚物的局部构象，并估计所选蛋白质受体的最佳结构。此外，他们还将探索寡氧哌嗪作为DNA主槽靶点的潜力。通过这一奖项，这些研究人员将展示计算和合成设计原则，以及开发新的生物活性化合物的合成有机方法。这种方法将产生仿生低聚物，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：在保留手性主链和侧链功能的同时，提供由氨基酸组装的非肽低聚物的途径。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。研究团队的成员将包括研究生和本科生，也来自代表性不足的群体。接受过该项目培训的学生可能会继续在制药或生物技术行业或学术界工作，从而为美国的科学努力和经济做出贡献。阿罗拉和博诺教授将继续通过组织研讨会，讨论化学和生物相结合的研究和教学进展，来吸引在以少数族裔为主的机构任教的教育工作者。

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.