Genomics-driven derivatization of the bioactive fungal sesterterpenoid variecolin:Creation of an unnatural analogue with improved anticancer properties  

作　　者：Dexiu Yan Jemma Arakelyan Teng Wan Ritvik Raina Tsz Ki Chan Dohyun Ahn Vladimir Kushnarev Tsz Kiu Cheung Ho Ching Chan Inseo Choi Pui Yi Ho Feijun Hu Yujeong Kim Hill Lam Lau Ying Lo Law Chi Seng Leung Chun Yin Tong Kai Kap Wong Wing Lam Yim Nikolay S.Karnaukhov Richard Y.C.Kong Maria V.Babak Yudai Matsuda 

机构地区：[1]Department of Chemistry,City University of Hong Kong,Hong Kong SAR,China [2]iGEM Team“VarieCure”,City University of Hong Kong,Hong Kong SAR,China [3]Department of Biomedical Engineering,City University of Hong Kong,Hong Kong SAR,China [4]Moscow Clinical Research Center Named After A.S.Loginov,Moscow 111123,Russian Federation

出　　处：《Acta Pharmaceutica Sinica B》2024年第1期421-432,共12页药学学报（英文版）

基　　金：This work was performed for the iGEM 2021 Competition,and the financial support received from the Department of Chemistry,City University of Hong Kong,is greatly appreciated.We also thank Prof.Katsuya Gomi(Tohoku University)and Profs.Katsuhiko Kitamoto and Jun-ichi Maruyama(The University of Tokyo)for providing the expression vectors and the fungal strain.We are grateful to Dr.Man-Kit Tse(City University of Hong Kong)and Dr.Shek-Man Yiu(City University of Hong Kong)for their assistance with NMR spectra acquisition and X-ray diffraction data collection and analysis,respectively.This work was supported in part by an Early Career Scheme grant from the Research Grants Council(RGC)of Hong Kong(Project No.21300219(Y.M));M.V.B acknowledges support from the City University of Hong Kong(Project No.9610518).

摘　　要：A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin(1)and variecolactone(2)was identified in Aspergillus aculeatus ATCC 16872.Heterologous production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB.Intriguingly,the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues(5-7).Analysis of the compounds’anticancer activity in vitro and in vivo revealed that although 5 and 1 had comparable activities,5 was associated with significantly reduced toxic side effects in cancer-bearing mice,indicating its potentially broader therapeutic window.Our study describes the first tests of variecolin and its analogues in animals and demonstrates the utility of synthetic biology for creating molecules with improved biological activities.

关 键 词：Animal studies Anticancer properties BIOSYNTHESIS Natural products Sesterterpenoids Synthetic biology Terpene synthases Variecolin 

分 类 号：R96[医药卫生—药理学]