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

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

  • Ritvik Raina
  • Tsz ki Chan
  • Dohyun Ahn
  • Vladimir Kushnarev
  • Tsz Kiu Cheung
  • Ho Ching Chan
  • Inseo Choi
  • Pui Yi Ho
  • Feijun Hu
  • Yujeong Kim
  • Ying Lo Law
  • Chi Seng Leung
  • Chun Yin Tong
  • Kai Kap Wong
  • Wing Lam Yim
  • Nikolay S. Karnaukhov
  • Maria V. Babak
  • Yudai Matsuda

Detail(s)

Original languageEnglish
Journal / PublicationActa Pharmaceutica Sinica B
Online published30 Aug 2023
Publication statusOnline published - 30 Aug 2023

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 (5e7). 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.

© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V

Research Area(s)

  • Animal studies, Anticancer properties, Biosynthesis, Natural products, Sesterterpenoids

Citation Format(s)

Genomics-driven derivatization of the bioactive fungal sesterterpenoid variecolin: Creation of an unnatural analogue with improved anticancer properties. / Yan, Dexiu; Arakelyan, Jemma; Wan, Teng et al.
In: Acta Pharmaceutica Sinica B, 30.08.2023.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review