Development of Macrocyclic Organo-Peptide Hybrids for Selective Targeting of Protein-Protein Interfaces

荣获该奖项的生命过程化学项目支持罗切斯特大学的鲁迪·法桑教授研究作为选择性靶向蛋白质界面的化学试剂的大环有机多肽杂交物(MOMs)的设计、合成和功能选择。这项研究将探索和实施这一新的方法，通过合成前体和遗传编码的多肽之间的化学选择性反应来产生有机多肽大环。图书馆的多样性将受益于包括合成的有机和编码的结构变化的多肽成分。这一用于配体组装和多样化的通用策略将与大肠杆菌中的展示系统和大环库的高通量筛选系统相结合。作为测试这种化学生物学方法的平台，将筛选氢化环肽文库，以选择性地调节肿瘤抑制蛋白P53与其抑制物HdmX和Hdm2之间的蛋白质复合体的形成。这种模块化有机多肽文库的生成和筛选方法，如果成功，将在化学生物学领域得到广泛的应用。此外，如果选择性Hdm2/HdmX靶向分子被鉴定出来，这些分子很可能成为研究细胞生理学和癌症生物学中P53通路调控/信号转导的有用的化学生物学工具。这个跨学科的研究项目将使研究生和本科生接触到有机化学、生物学和生物物理学的技术。该项目还将吸引传统上代表性不足的群体成员参与化学-生物界面的科学研究。

With this award, the Chemistry of Life Processes program is supporting Professor Rudi Fasan at the University of Rochester to investigate the design, synthesis, and functional selection of macrocyclic organo-peptide hybrids (MOrPHs) as chemical agents for selectively targeting protein interfaces. This research will investigate and implement this new methodology for generating organo-peptide macrocycles via a chemoselective reaction between synthetic precursors and genetically encoded polypeptides. Library diversity will benefit from the inclusion of both synthetic organic and encoded peptidyl elements of structural variation. This versatile strategy for ligand assembly and diversification will be coupled to a display system in E. coli and a high throughput screening system for the macrocycle libraries. As a platform to test this approach to chemical biology, the hydrid cyclic peptide libraries will be screened for the selective modulation of protein complex formation between the tumor suppressor protein, p53, and its repressors HdmX and Hdm2. This approach to modular organo-peptide library generation and screening, if successful, could find broad application in the field of Chemical Biology. Moreover, if selective Hdm2/HdmX-targeting molecules are identified these would likely serve as useful chemical biological tools for the study of regulation/signal transduction in the p53 pathway in cell physiology and cancer biology. This cross-disciplinary research project will expose graduate and undergraduate students to techniques in organic chemistry, biology, and biophysics. The project will also engage members of traditionally underrepresented groups in scientific research at the chemistry-biology interface.