Macrocyclic Peptide Modulators of Protein Function

蛋白质功能的大环肽调节剂

基本信息

批准号：
10470247
负责人：
Rudi Fasan
金额：
$ 13.38万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10470247
关键词：
Address Affinity Amino Acyl-tRNA Synthetases Bacteriophage M13 Binding Biology Biomedical Research Cell physiology Cells Chemical Agents Chemicals Cyclic Peptides Cyclization Detection Development Disease Doctor of Philosophy Effectiveness Enzymes Eukaryotic Cell Generations Genetic Guidelines Human Hybrids Investigation Label Lead Libraries Ligands Mammalian Cell Mediating Membrane Proteins Methodology Methods Molecular Molecular Conformation Natural Products PD-1 inhibitors PD-1/PD-L1 Pathway interactions Peptide Synthesis Peptides Phage Display Pharmaceutical Preparations Phenotype Process Proteins Rapid screening Reagent Recombinants Research Role Signal Pathway Signaling Protein Sonication Source Specificity Structure System Technology Therapeutic Yeasts analog base drug development drug discovery drug structure inhibitor innovation polypeptide protein function protein phosphatase inhibitor-2 protein protein interaction scaffold screening small molecule smoothened signaling pathway therapeutic development therapeutic target tool unnatural amino acids yeast two hybrid system

项目摘要

Macrocyclic Peptide Modulators of Protein Function Progress toward an understanding of protein-mediated interactions involved in cell physiology and disease heavily relies on the availability of chemical agents capable of targeting and modulating protein function with high potency and selectivity. While small-molecule agents have provided a major source of chemical probes and therapeutics, an overwhelming fraction of human proteins and protein-mediated interactions remains impervious to modulation using this class of molecules, posing a fundamental barrier to efforts directed at elucidating their role in physiopathological processes and assessing their therapeutic potential. Our group has recently introduced an efficient and highly versatile methodology for generating small-size, genetically encoded macrocyclic peptides in living cells and demonstrated the effectiveness of these 'natural product-like' compounds to disrupt a challenging protein-protein interaction with high potency and specificity. In this project, this versatile methodology for macrocyclic peptide synthesis will be integrated with phage display and cell-based selection systems in order to implement powerful, high-throughput platforms for the rapid discovery of potent and selective macrocyclic peptide modulators of proteins and protein-protein interactions. Successful completion of this research is expected to make available new, efficient, and readily accessible technologies useful for developing macrocyclic peptide agents capable of modulating protein function with high potency and selectivity across a wide range of target proteins and cellular processes. As such, these technologies are bound to streamline the development of chemical probes for interrogating cellular pathways and validating therapeutic targets, the generation of selective reagents for protein detection and labeling, and the identification of potential lead structures for drug development, thereby accelerating efforts in basic biomedical research, chemical biology, and drug discovery.

蛋白质功能的大环肽调节剂对细胞生理学和疾病中蛋白质介导的相互作用的理解取得进展很大程度上依赖于能够靶向和调节蛋白质功能的化学试剂的可用性高效力和选择性。虽然小分子试剂提供了化学探针的主要来源，治疗方面，绝大多数人类蛋白质和蛋白质介导的相互作用仍然是不可渗透的使用此类分子进行调节，对阐明其分子的努力构成了根本障碍在病理生理过程中的作用并评估其治疗潜力。我们组最近推出了一种高效且高度通用的方法，用于生成小尺寸、基因编码的大环肽在活细胞中，并证明了这些“类似天然产品”的化合物能够有效破坏具有高效力和特异性的挑战性蛋白质-蛋白质相互作用。在这个项目中，这种多功能的方法用于大环肽合成的方法将与噬菌体展示和基于细胞的选择系统集成，以便实施强大的高通量平台，以快速发现有效且选择性的大环化合物蛋白质和蛋白质-蛋白质相互作用的肽调节剂。本研究的顺利完成预计将提供可用于开发的新的、高效的、易于获取的技术能够高效、选择性调节蛋白质功能的大环肽制剂涵盖广泛的靶蛋白和细胞过程。因此，这些技术必然会简化用于询问细胞途径和验证治疗的化学探针的开发目标、用于蛋白质检测和标记的选择性试剂的生成以及潜力的识别药物开发的先导结构，从而加速基础生物医学研究、化学研究的努力生物学和药物发现。