Acta Pharmaceutica Sinica B (Jan 2024)
Genomics-driven derivatization of the bioactive fungal sesterterpenoid variecolin: Creation of an unnatural analogue with improved anticancer properties
- 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
Affiliations
- Dexiu Yan
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Jemma Arakelyan
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Teng Wan
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Ritvik Raina
- iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China; Department of Biomedical Engineering, City University of Hong Kong, Hong Kong SAR, China
- Tsz Ki Chan
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Dohyun Ahn
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Vladimir Kushnarev
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China
- Tsz Kiu Cheung
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Ho Ching Chan
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Inseo Choi
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Pui Yi Ho
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Feijun Hu
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Yujeong Kim
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Hill Lam Lau
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Ying Lo Law
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Chi Seng Leung
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Chun Yin Tong
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Kai Kap Wong
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Wing Lam Yim
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China
- Nikolay S. Karnaukhov
- Moscow Clinical Research Center Named After A.S. Loginov, Moscow 111123, Russian Federation
- Richard Y.C. Kong
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China; Corresponding authors.
- Maria V. Babak
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China; Corresponding authors.
- Yudai Matsuda
- Department of Chemistry, City University of Hong Kong, Hong Kong SAR, China; iGEM Team “VarieCure”, City University of Hong Kong, Hong Kong SAR, China; Corresponding authors.
- Journal volume & issue
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Vol. 14,
no. 1
pp. 421 – 432
Abstract
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.
