A Semisynthesis Platform for the Efficient Production and Exploration of Didemnin-Based Drugs

Zhang，Haili1; Li，Xuyang1; Hui，Zhen1; Huang，Shipeng1,2; Cai，Mingwei1; Shi，Wenguang1; Lin，Yang1; Shen，Jie3; Sui，Minghao3; Lai，Qiliang4; Shao，Zongze4; Dou，Jie3; Luo，Xiaozhou5; Ge，Yun1,6; Tang，Xiaoyu1

2024-03-18

10.1002/anie.202318784

Angewandte Chemie - International Edition   影响因子和分区

1433-7851

1521-3773

Plitidepsin (or dehydrodidemnin B), an approved anticancer drug, belongs to the didemnin family of cyclic depsipeptides, which are found in limited quantities in marine tunicate extracts. Herein, we introduce a new approach that integrates microbial and chemical synthesis to generate plitidepsin and its analogues. We screened a Tistrella strain library to identify a potent didemnin B producer, and then introduced a second copy of the didemnin biosynthetic gene cluster into its genome, resulting in a didemnin B titer of approximately 75 mg/L. Next, we developed two straightforward chemical strategies to convert didemnin B into plitidepsin, one of which involved a one-step synthetic route giving over 90 % overall yield. Furthermore, we synthesized 13 new didemnin derivatives and three didemnin probes, enabling research into structure–activity relationships and interactions between didemnin and proteins. Our study highlights the synergistic potential of biosynthesis and chemical synthesis in overcoming the challenge of producing complex natural products sustainably and at scale.

biosynthesis depsipeptides marine drugs palmitoyl protein thioesterase 1 semisynthesis

SCI ; EI

英语

其他

CHEMISTRY

2-s2.0-85185113196

Scopus

1.Institute of Chemical Biology,Shenzhen Bay Laboratory,Shenzhen,518132,China
2.Department of Chemistry and Shenzhen Grubbs Institute,Southern University of Science and Technology,Shenzhen,518000,China
3.College of Life Science and Technology,China Pharmaceutical University,Nanjing,211198,China
4.Key Laboratory of Marine Genetic Resources,Third Institute of Oceanography,Ministry of Natural Resources,Xiamen,184 Daxue Road,361005,China
5.Center for Synthetic Biochemistry,Shenzhen Institute of Synthetic Biology,Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen,518055,China
6.State Key Laboratory of Chemical Oncogenomics,School of Chemical Biology and Biotechnology,Peking University Shenzhen Graduate School,Shenzhen,518055,China

Zhang，Haili,Li，Xuyang,Hui，Zhen,et al. A Semisynthesis Platform for the Efficient Production and Exploration of Didemnin-Based Drugs[J]. Angewandte Chemie - International Edition,2024,63(12).

Zhang，Haili.,Li，Xuyang.,Hui，Zhen.,Huang，Shipeng.,Cai，Mingwei.,...&Tang，Xiaoyu.(2024).A Semisynthesis Platform for the Efficient Production and Exploration of Didemnin-Based Drugs.Angewandte Chemie - International Edition,63(12).

Zhang，Haili,et al."A Semisynthesis Platform for the Efficient Production and Exploration of Didemnin-Based Drugs".Angewandte Chemie - International Edition 63.12(2024).