In Vitro Selection of Macrocyclic d/l‑Hybrid Peptides against Human EGFR

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.

D/L型杂合肽（d/l-hybrid peptides）是一类极具吸引力的分子模态，因其可兼具高蛋白水解稳定性与独特的结构多样性——此类特性是仅由蛋白源性L型氨基酸构成的肽类所无法具备的。尽管有着此类应用潜力，但由于缺乏能够可靠构建高多样性文库并筛选活性分子的有效方法，目前尚无法设计出可破坏靶蛋白功能的从头合成D/L型杂合肽。本文首次报道了包含五种D型氨基酸的10¹²个大环D/L型杂合肽文库的构建，并以针对人表皮生长因子受体（epidermal growth factor receptor, EGFR）的RaPID筛选作为示例，成功挖掘得到蛋白质-蛋白质相互作用（protein–protein interaction, PPI）抑制剂。