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，纽约大学化学系和生物系的Paramjit Arora教授和Richard Bonneau教授将研究可以调节选定蛋白质功能的蛋白质子域的合成模拟物。目标包括非肽低聚物，模拟α -螺旋构象和显示类似蛋白质的功能。将使用标准程序从天然和非天然氨基酸合成氧哌嗪类螺旋低聚物。研究人员将开发实验和计算方法来筛选针对模型蛋白目标的非肽螺旋模拟物文库，以识别高亲和力，选择性配体。他们将实现计算工具，可以准确地预测非肽寡聚物的局部构象，并估计所选蛋白质受体的最佳结构。此外，他们将探索低聚哌嗪靶向DNA主槽的潜力。有了这个奖项，这些研究人员将展示计算和合成设计原理，以及合成有机方法来开发新型生物活性化合物。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：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。研究小组的成员将包括研究生和本科生，也将从代表性不足的群体中抽取。参加该项目的学生可能会在制药或生物技术行业或学术界从事职业，从而为美国的科学事业和经济做出贡献。阿罗拉教授和博诺教授将继续组织研讨会，讨论化学和生物学交叉领域的研究和教学进展，从而吸引在少数族裔机构任教的教育工作者。

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.