日本东京大学Hiroaki Suga团队报道了抗人EGFR大环d/l杂交肽的体外筛选策略。 相关研究成果于2021年4月6日发表在国际顶尖学术期刊《美国化学会杂志》。

d/l-杂合肽是一类很有吸引力的分子形式，因为它们具有高的蛋白水解稳定性和独特的结构多样性，但这些无法仅由蛋白源性l-氨基酸组成而获得。尽管有这样的期望，但由于缺乏可靠地构建高度多样性文库和筛选活性物种的有效方法，尚不可能设计出能够破坏蛋白质靶标功能的从头d/l-杂交肽。

该文中，研究人员首次构建了一个由1012个含有5种d-氨基酸的大环d/l-杂合肽组成的文库，并对人表皮生长因子受体进行了快速筛选，以此展示PPI（蛋白质-蛋白质相互作用）抑制剂的发现。

附：英文原文

Title: In Vitro Selection of Macrocyclic d/l-Hybrid Peptides against Human EGFR

Author: Sayaka Imanishi, Takayuki Katoh, Yizhen Yin, Mituhiro Yamada, Marina Kawai, Hiroaki Suga

Issue&Volume: April 6, 2021

Abstract: d/l-Hybrid peptides are an attractive class of molecular modality because they are able to exhibit high proteolytic stability and unique structural diversity which cannot be accessed by those consisting of only proteinogenic l-amino acids. Despite such an expectation, it has not been possible to devise de novo d/l-hybrid peptides capable of disrupting the function of a protein target(s) due to the lack of an effective method that reliably constructs a highly diverse library and screens active species. Here we report for the first time construction of a library consisting of 1012 members of macrocyclic d/l-hybrid peptides containing five kinds of d-amino acids and performance of the RaPID selection against human EGFR as a showcase to uncover PPI (protein–protein interaction) inhibitors.

DOI: 10.1021/jacs.1c02593

Source: https://pubs.acs.org/doi/10.1021/jacs.1c02593