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, Владимир Кушнарев, 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 Karnaukhov, Richard Yuen Chong Kong, Maria V. Babak, Yudai Matsuda
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.