针对蛋白-蛋白相互作用增强肽治疗的环环化方法的进展

IF 3.6 2区 化学 Q1 CHEMISTRY, ORGANIC
Lucia Lombardi, Luke A. Granger, Robin J. Shattock, Daryl R. Williams
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引用次数: 0

摘要

蛋白质-蛋白质相互作用(PPIs)在调节细胞功能和生命过程中起着至关重要的作用,使其成为现代医学中有希望的治疗靶点。尽管具有潜力,但由于其大而浅的界面使配体结合复杂化,开发PPI抑制剂面临重大挑战。本研究的重点是模仿肽环作为抑制PPI的策略,利用合成肽环复制关键结合区域。这项工作探索了转向诱导元素,并强调了脯氨酸在促进内酰胺化有利构象中的重要性,从而产生高纯度的环肽。值得注意的是,我们的一锅方法提供了增强的通用性,代表了高效和选择性大内酰胺化的稳健策略,扩大了肽合成方法的范围。这种方法通过AAV衣壳衍生环的合成得到验证,为开发基于肽的治疗方法提供了一个强大的平台,并突出了肽大环在克服PPI药物发现挑战和推进新治疗方法开发方面的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Advancements in Loop Cyclization Approaches for Enhanced Peptide Therapeutics for Targeting Protein–Protein Interactions

Advancements in Loop Cyclization Approaches for Enhanced Peptide Therapeutics for Targeting Protein–Protein Interactions
Protein–protein interactions (PPIs) are pivotal in regulating cellular functions and life processes, making them promising therapeutic targets in modern medicine. Despite their potential, developing PPI inhibitors poses significant challenges due to their large and shallow interfaces that complicate ligand binding. This study focuses on mimicking peptide loops as a strategy for PPI inhibition, utilizing synthetic peptide loops for replicating critical binding regions. This work explores turn-inducing elements and highlights the importance of proline in promoting favorable conformations for lactamization, yielding high-purity cyclic peptides. Notably, our one-pot method offers enhanced versatility and represents a robust strategy for efficient and selective macrolactamization, expanding the scope of peptide synthesis methodologies. This approach, validated through the synthesis of AAV capsid-derived loops, offers a robust platform for developing peptide-based therapeutics and highlights the potential of peptide macrocycles in overcoming PPI drug discovery challenges and advancing the development of new therapeutics.
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来源期刊
Journal of Organic Chemistry
Journal of Organic Chemistry 化学-有机化学
CiteScore
6.20
自引率
11.10%
发文量
1467
审稿时长
2 months
期刊介绍: Journal of Organic Chemistry welcomes original contributions of fundamental research in all branches of the theory and practice of organic chemistry. In selecting manuscripts for publication, the editors place emphasis on the quality and novelty of the work, as well as the breadth of interest to the organic chemistry community.
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