Macrocyclic Peptide Modulators of Protein Function

蛋白质功能的大环肽调节剂

• 批准号: 10000964
• 负责人: Rudi Fasan
• 金额: $ 28.41万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000964
• 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; 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/antagonist; 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

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 细胞生理学和疾病中蛋白质介导的相互作用的研究进展 严重依赖于能够靶向和调节蛋白质功能的化学试剂的可用性， 高效性和选择性。虽然小分子试剂提供了化学探针的主要来源， 在治疗学上，绝大多数人类蛋白质和蛋白质介导的相互作用仍然不受影响， 使用这类分子的调制，构成了一个根本性的障碍，旨在阐明他们的努力， 在病理生理过程中的作用，并评估其治疗潜力。我们集团最近推出了 用于产生小尺寸的、遗传编码的大环肽的高效且高度通用的方法 在活细胞中，并证明了这些“天然产物样”化合物的有效性， 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， 大环肽的合成将与噬菌体展示和基于细胞的选择系统相结合， 实施强大的高通量平台，用于快速发现有效和选择性的大环 蛋白质和蛋白质-蛋白质相互作用的肽调节剂。成功完成这项研究是 预计将提供新的，有效的，易于获得的技术，用于发展 能够以高效力和选择性调节蛋白质功能的大环肽试剂 广泛的靶蛋白和细胞过程。因此，这些技术必然会 简化化学探针的开发，用于询问细胞通路和验证治疗 目标，用于蛋白质检测和标记的选择性试剂的产生，以及潜在的 领导药物开发结构，从而加快基础生物医学研究、化学 生物学和药物发现。