日本东京大学Suga Hiroaki团队报道了翻译后骨架酰基移位产生含Hhc单元天然产物样肽，含有羟基烃单位。相关研究成果于2022年11月3日发表在国际顶尖学术期刊《自然—化学》。

肽天然产物骨架中的羟基烃（Hhc）部分可以对产物的生物活性产生重大影响，使Hhc单元成为从头合成肽的一类有吸引力的构建块。然而，尽管在体外遗传密码重编程方面取得了进展，Hhc单位的核糖体掺入仍然具有挑战性。

该文中，研究人员报道了一种体外核糖体合成含Hhc单元天然产物样肽的方法。设计了一系列叠氮/羟基酸作为Hhc单元的化学前体，并通过遗传密码重编程将其并入新生肽链。叠氮化物的翻译后还原诱导O-N酰基转移以重排肽骨架。该方法能够一锅核糖体合成含有各种β-、γ-和δ-型Hhc单元的设计大环。研究人员还报道了一种含他汀类β-分泌酶1拟肽抑制剂的合成，作为一个展示性例子。

附：英文原文

Title: Post-translational backbone-acyl shift yields natural product-like peptides bearing hydroxyhydrocarbon units

Author: Kuroda, Tomohiro, Huang, Yichao, Nishio, Soichiro, Goto, Yuki, Suga, Hiroaki

Issue&Volume: 2022-11-03

Abstract: Hydroxyhydrocarbon (Hhc) moieties in the backbone of peptidic natural products can exert a substantial influence on the bioactivities of the products, making Hhc units an attractive class of building blocks for de novo peptides. However, despite advances in in vitro genetic code reprogramming, the ribosomal incorporation of Hhc units remains challenging. Here we report a method for in vitro ribosomal synthesis of natural-product-like peptides bearing Hhc units. A series of azide/hydroxy acids were designed as chemical precursors of Hhc units and incorporated into the nascent peptide chain by means of genetic code reprogramming. Post-translational reduction of the azide induced an O-to-N acyl shift to rearrange the peptide backbone. This method allows for one-pot ribosomal synthesis of designer macrocycles bearing various β-, γ- and δ-type Hhc units. We also report the synthesis of a statine-containing peptidomimetic inhibitor of β-secretase 1 as a showcase example.

DOI: 10.1038/s41557-022-01065-1

Source: https://www.nature.com/articles/s41557-022-01065-1