Post-translational backbone-acyl shift yields natural product-like peptides bearing hydroxyhydrocarbon units
Post-translational backbone-acyl shift yields natural product-like peptides bearing hydroxyhydrocarbon units
复制标题
翻译后主链酰基转移产生带有羟基烃单元的类似天然产物的肽
DOI：
10.1038/s41557-022-01065-1
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发表时间：
2022
期刊：
影响因子：
21.8
通讯作者：
Suga Hiroaki
中科院分区：
文献类型：
--
作者：
Kuroda Tomohiro;Huang Yichao;Nishio Soichiro;Goto Yuki;Suga Hiroaki
肽类天然产物主链中的羟基烃 (Hhc) 部分可以对产品的生物活性产生重大影响，使 Hhc 单元成为一种有吸引力的从头肽构建模块。然而，尽管体外遗传密码重编程取得了进展，Hhc 单位的核糖体掺入仍然具有挑战性。在这里，我们报告了一种体外核糖体合成带有 Hhc 单位的类似天然产物的肽的方法。一系列叠氮化物/羟基酸被设计为Hhc单元的化学前体，并通过遗传密码重编程的方式整合到新生肽链中。叠氮化物的翻译后还原诱导 O 向 N 酰基转变，从而重新排列肽主链。该方法允许一锅核糖体合成带有各种 β-、γ- 和 δ- 型 Hhc 单元的设计大环化合物。我们还报道了 β-分泌酶 1 的含他汀类肽模拟抑制剂的合成作为展示示例。
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 anO-to-Nacyl 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.