美国华盛顿大学David Baker团队报道了化学结构多样的大环低聚酰胺的广泛发现。相关研究成果于2024年4月26日发表于国际一流学术期刊《科学》。

具有四个或更少氨基酸的小大环是已知的最有效的天然产物之一，但目前还没有办法系统地制备这种化合物。

研究人员描述了一种识别由α、β、γ和17种其他氨基酸主链化学组成的有序大环的计算方法，用它来预测1490万个由>42000个单体组合组成的闭合环。研究人员化学合成了18个预测采用单一低能态的大环，并确定了它们的x射线或核磁共振结构，其中15个与设计模型非常接近。

研究人员通过开发目前感兴趣的三种蛋白质靶标的选择性抑制剂，来说明这些大环设计的治疗潜力。通过开辟易于合成的药物类大环的广阔空间表明，研究结果应该会大大增强基于结构的药物设计。

附：英文原文

Title: Expansive discovery of chemically diverse structured macrocyclic oligoamides

Author: Patrick J. Salveson, Adam P. Moyer, Meerit Y. Said, Gizem Gke, Xinting Li, Alex Kang, Hannah Nguyen, Asim K. Bera, Paul M. Levine, Gaurav Bhardwaj, David Baker

Issue&Volume: 2024-04-26

Abstract: Small macrocycles with four or fewer amino acids are among the most potent natural products known, but there is currently no way to systematically generate such compounds. We describe a computational method for identifying ordered macrocycles composed of alpha, beta, gamma, and 17 other amino acid backbone chemistries, which we used to predict 14.9 million closed cycles composed of >42,000 monomer combinations. We chemically synthesized 18 macrocycles predicted to adopt single low-energy states and determined their x-ray or nuclear magnetic resonance structures; 15 of these were very close to the design models. We illustrate the therapeutic potential of these macrocycle designs by developing selective inhibitors of three protein targets of current interest. By opening up a vast space of readily synthesizable drug-like macrocycles, our results should considerably enhance structure-based drug design.

DOI: adk1687

Source: https://www.science.org/doi/10.1126/science.adk1687