近日，德国莱布尼茨天然产物研究和感染生物学研究所教授Christian Hertweck及其课题组，报道了捕获释放策略用于基因组学驱动的发现抗增殖呋喃功能化肽。相关论文于2024年12月16日发表在《德国应用化学》杂志上。

据介绍，呋喃功能化肽由于显著的生物活性和独特的正交生物偶联和衍生化潜力，具有重要的药理学意义。然而，具有呋喃基侧链的天然肽是非常罕见的。

本研究提出了一种简化的方法来预测和评估含有3-呋喃丙氨酸（Fua）片段的肽的微生物生产。该方法整合了基因组挖掘和可逆的，呋喃基残基的化学选择性标记，利用其独特的Diels-Alder反应性，用于质谱指导的候选化合物鉴定。

课题组人员以根瘤菌素Fua合成酶为生物信息学柄，通过对Fua生物合成的异源重组，在放线菌、蓝藻、放线菌门和g-变形菌等不同细菌门中，发现了此前未知的Fua生物合成途径，表明含Fua肽的分布非常广泛。

可逆标记的代谢谱分析有助于检测天然含Fua代谢物。这种方法的成功适应固相载体，使得从复杂混合物中直接富集呋喃基取代肽成为可能。这种多管齐下的方法帮助发现和表征了两个新的Fua的环肽家族 （红酰胺和鼠苯酰胺），它们对人类肿瘤细胞和线虫具有有效的抗增殖作用。创新的捕获和释放策略，与基因组挖掘相结合，是发现新的呋喃替代天然产物的宝贵工具。

附：英文原文

Title: A Catch-Release Strategy for the Genomics-Driven Discovery of Antiproliferative Furan-Functionalized Peptides

Author: Friedrich J. Ehinger, Kirstin Scherlach, Felix Trottmann, Jonas Fiedler, Christian Hertweck

Issue&Volume: 2024-12-16

Abstract: Abstract: Furan-functionalized peptides are of significant pharmacological interest due to their pronounced bioactivities and unique potential for orthogonal bioconjugation and derivatization. However, naturally occurring peptides with furyl side chains are exceedingly rare. This study presents a streamlined method to predict and assess the microbial production of peptides incorporating 3-furylalanine (Fua) moieties. The approach integrates genome mining and the reversible, chemoselective tagging of furyl residues, utilizing their unique Diels-Alder reactivity, for mass spectrometry-guided identification of candidate compounds. By employing the rhizonin Fua synthase as a bioinformatic handle and through heterologous reconstitution of Fua biosynthesis, we identified previously unknown Fua biosynthetic pathways in diverse bacterial phyla, including actinomycetes, cyanobacteria, actinobacteria, and g-proteobacteria, suggesting that Fua-containing peptides are remarkably widely distributed. Metabolic profiling by reversible tagging facilitated the detection of native Fua-containing metabolites. The successful adaptation of this method for solid support enabled the direct enrichment of furyl-substituted peptides from complex mixtures. This multi-pronged approach enabled the discovery and characterization of two novel families of Fua cyclopeptides (rubriamides and typhamides) with potent antiproliferative effects against human tumor cells and nematodes. The innovative catch-and-release strategy, in conjunction with genome mining, represents a valuable tool for the discovery of new furan-substituted natural products.

DOI: 10.1002/anie.202421760

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202421760