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. KarnaukhovRichard Y.C. Kong*, Maria V. Babak*, Yudai Matsuda*

*Corresponding author for this work

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

6 Citations (Scopus)
19 Downloads (CityUHK Scholars)

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 (57). 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. © 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Original languageEnglish
Pages (from-to)421-432
JournalActa Pharmaceutica Sinica B
Volume14
Issue number1
Online published30 Aug 2023
DOIs
Publication statusPublished - Jan 2024

Research Keywords

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

Publisher's Copyright Statement

  • This full text is made available under CC-BY-NC-ND 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/

Fingerprint

Dive into the research topics of 'Genomics-driven derivatization of the bioactive fungal sesterterpenoid variecolin: Creation of an unnatural analogue with improved anticancer properties'. Together they form a unique fingerprint.

Cite this