Integration of microbial and chemical synthesis for the efficient production of plitidepsin, a promising anticancer and antiviral agent
Zhang, H.; Hui, Z.; Cai, M.; Huang, S.; Shi, W.; Liang, M.; Lin, Y.; Shen, J.; Sui, M.; Li, X.; Lai, Q.; Dou, J.; Ge, Y.; Zheng, M.; Shao, Z.; Lou, X.; Tang, X.
Show abstract
Plitidepsin, a marine-derived anticancer medicine, is being tested in phase III clinical trials for treating COVID-19. However, the current supply of plitidepsin relies on laborious chemical synthesis processes. Here, we present a new approach that combines microbial and chemical synthesis to produce plitidepsin. We screened a Tistrella strain library to identify a high-yield didemnin B producer, and then introduced a second copy of the didemnin biosynthetic gene cluster into its genome, resulting in the highest yield of didemnin B reported in the literature. Next, we developed two straightforward chemical strategies to convert didemnin B to plitidepsin, one of which involved a one-step synthetic route giving over 90% overall yield. We also synthesized two new didemnin analogues and assessed their anticancer and antiviral activities. Our findings offer a practical and sustainable solution for producing plitidepsin and its derivatives, potentially expediting didemnin drug development.
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