Discovery, Biomanufacture, and Derivatization of Licorice Triterpenoids.

Triterpenoids are the major active constituents of licorice, a well-known traditional medicinal herb. Licorice triterpenoids, represented by glycyrrhizin and glycyrrhetic acid, have a high structural diversity and are excellent lead compounds for the development of potent pharmaceuticals. However, their further application can be limited by insufficient activities, low bioavailability, and the presence of side effects, as well as the inefficiency of traditional plant extraction processes for compound production. To address these issues, researchers are focusing on rare triterpenoid components in the genus and developing derivatives to preserve or enhance the original physiological activities with improved bioavailability and reduced side effects. At the same time, synthetic biology offers opportunities to shorten the production cycle, create eco-friendly manufacturing processes, and reduce the cost of producing licorice triterpenoids. Although much progress has been achieved in this field in recent years, there is still a lack of a comprehensive review to summarize the overall characteristics of licorice triterpenoids rather than glycyrrhizin and glycyrrhetinic acid. Based on this, our review comprehensively outlines the structures, origins, and pharmacological activities of licorice triterpenoids and predicts their pharmacological activities using the drugCIPHER algorithm. Furthermore, this paper reviews the advances and strategies for the biomanufacturing of licorice triterpenoids using synthetic biology methods and outlines the perspectives and structure-activity relationships for the derivatization of licorice triterpenoids. This review provides new insights into the discovery and synthesis of pharmaceuticals derived from natural triterpenes.