近日，浙江大学李承喜团队实现了通过二氨基烟酸支架自动快速合成高纯度首尾环肽。该项研究成果发表在2025年12月22日出版的《美国化学会志》上。

环肽独特地融合了生物制剂的结构稳定性与靶向特异性，以及小分子的合成灵活性。然而，其化学合成在速度和效率上长期落后于核糖体合成途径。

研究组报道了CycloBot——一个专为全自动化、分钟级组装环肽而设计的机器人平台。该平台在接近核糖体生物合成通量的同时，能够兼容天然与非天然氨基酸。这一突破的核心在于采用二氨基烟酸（DAN）支架，可在树脂上实现“一键式”同步环化/切割的头尾环合，从而制备不同尺寸的大环化合物，产率高达93%，粗产物纯度超过95%，且副产物差向异构化程度极低。

通过该平台在1天内快速构建包含20个成员的抗菌环肽库，充分证明了其应用价值：其中先导化合物对金黄色葡萄球菌和枯草芽孢杆菌的抗菌活性相较于青霉素增强了100倍。该技术成功融合了核糖体合成的速度优势与化学合成的结构多样性，为加速个性化环肽疗法的发现与开发建立了新范式。

附：英文原文

Title: Automated Rapid Synthesis of High-Purity Head-to-Tail Cyclic Peptides via a Diaminonicotinic Acid Scaffold

Author: Feng Wan, Chengrui Hu, Pei Xie, Xingxing Yang, Xin He, Yourong Pan, Zuozhou Ning, Chengxi Li

Issue&Volume: December 22, 2025

Abstract: Cyclic peptides uniquely integrate the structural stability and target specificity of biologics with the synthetic versatility of small molecules. However, their chemical synthesis has historically lagged behind ribosomal production in both speed and efficiency. Herein, we present CycloBot, a robotic platform designed for fully automated, minute-scale assembly of cyclopeptides, approaching the throughput of ribosomal biosynthesis while accommodating both natural and non-natural amino acids. Central to this advancement is a diaminonicotinic acid (DAN) scaffold enabling “one-click”, concomitant cyclization/cleavage head-to-tail cyclization directly on resin, affording macrocycles of varying sizes with yields up to 93%, crude purities exceeding 95%, and minimal epimerization. The platform’s utility is exemplified by the rapid generation of a 20-member antimicrobial cyclic peptide library in 1 day, from which a lead candidate exhibited 100-fold enhanced antibacterial activity against S. aureus and B. subtilis relative to penicillin. By bridging the speed of ribosomal synthesis and the structural diversity accessible via chemical synthesis, this technology establishes a new paradigm for accelerated discovery and development of personalized cyclic peptide therapeutics.

DOI: 10.1021/jacs.5c16902

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.5c16902