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

开发用于选择性靶向蛋白质-蛋白质界面的大环有机肽杂化物

• 批准号: 1112342
• 负责人: Rudi Fasan
• 金额: $ 33万
• 依托单位: University of Rochester
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1112342&HistoricalAwards=false
• 关键词: Development; Macrocyclic; Organo; Peptide; Hybrids

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.

凭借该奖项，生命过程化学项目正在支持罗切斯特大学的 Rudi Fasan 教授研究大环有机肽杂化物 (MOrPH) 的设计、合成和功能选择，作为选择性靶向蛋白质界面的化学试剂。 这项研究将研究并实施这种通过合成前体和基因编码多肽之间的化学选择性反应生成有机肽大环化合物的新方法。文库多样性将受益于包含结构变异的合成有机元素和编码肽基元素。这种用于配体组装和多样化的多功能策略将与大肠杆菌中的展示系统和大环文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，将筛选杂环肽文库，以选择性调节肿瘤抑制蛋白 p53 及其阻遏蛋白 HdmX 和 Hdm2 之间的蛋白复合物形成。这种模块化有机肽库生成和筛选的方法如果成功的话，可以在化学生物学领域得到广泛的应用。 此外，如果鉴定出选择性 Hdm2/HdmX 靶向分子，这些分子可能会成为有用的化学生物学工具，用于研究细胞生理学和癌症生物学中 p53 途径的调节/信号转导。这个跨学科研究项目将使研究生和本科生接触有机化学、生物学和生物物理学的技术。该项目还将让传统上代表性不足的群体成员参与化学-生物学界面的科学研究。