Macrocyclic Peptide Modulators of Protein Function

蛋白质功能的大环肽调节剂 蛋白质介导的相互作用在细胞生理和疾病中的研究进展 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、高选择性。虽然小分子试剂提供了化学探针和 治疗，压倒性的人类蛋白质和蛋白质介导的相互作用仍然是不可渗透的 利用这类分子进行调制，这对旨在阐明它们的 在生理病理过程中的作用和评估其治疗潜力。我们小组最近介绍了 一种高效和高度通用的产生小尺寸、遗传编码大环肽的方法 并证明了这些类似天然产物的化合物能够有效地破坏一种 挑战高效和特异性的蛋白质-蛋白质相互作用。在这个项目中，这个通用的方法 对于大环肽合成，将依次与噬菌体展示和基于细胞的选择系统集成 实施功能强大的高通量平台，以快速发现有效和选择性的大环 蛋白质的多肽调节剂和蛋白质之间的相互作用。这项研究的成功完成是 期望使新的、高效的和易于访问的技术对开发有用 高效、选择性调节蛋白质功能的大环肽类药物 在广泛的目标蛋白质和细胞过程中。因此，这些技术必然会 简化用于询问细胞途径和验证治疗效果的化学探针的开发 靶标，蛋白质检测和标记的选择性试剂的产生，以及潜在的识别 领导药物开发机构，从而加快基础生物医学研究、化学 生物学和药物发现。

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.