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

• Published in: Angewandte Chemie International Edition 2024-03, Vol.63 (12), p.e202318784-n/a
• Main Authors: Zhang, Haili, Li, Xuyang, Hui, Zhen, Huang, Shipeng, Cai, Mingwei, Shi, Wenguang, Lin, Yang, Shen, Jie, Sui, Minghao, Lai, Qiliang, Shao, Zongze, Dou, Jie, Luo, Xiaozhou, Ge, Yun, Tang, Xiaoyu
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic drugs; Biosynthesis; Chemical synthesis; depsipeptides; Depsipeptides - pharmacology; DNA probes; Genomes; marine drugs; Marine invertebrates; Microorganisms; Natural products; palmitoyl protein thioesterase 1; Peptides, Cyclic - metabolism; Peptides, Cyclic - pharmacology; Semisynthesis; Structure-Activity Relationship
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202318784

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. A platform has been established for the exploration of didemnin‐based drugs, combining microbial synthesis of didemnin B through genetic engineering of Tistrella mobilis and semisynthesis for the production of plitidepsin for drug purposes, didemnin derivatives for studying structure–activity relationships, and didemnin B probes for targeted protein profiling. This sustainable approach holds potential for investigating other marine natural products.