2. Academic Validation
  3. A target and efficient synthetic strategy for structural and bioactivity optimization of a fungal natural product

A target and efficient synthetic strategy for structural and bioactivity optimization of a fungal natural product

  • Eur J Med Chem. 2022 Feb 5:229:114067. doi: 10.1016/j.ejmech.2021.114067.
Fei Cao 1,  Min-Kui Zhang 2,  Xi Yang 3,  Chu-Xuan Xu 1,  Jin-Tao Cheng 1,  Qing-Wei Zhao 2,  Rui Wu 4,  Rong Sheng 5,  Xu-Ming Mao 6
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences & Research Center for Clinical Pharmacy, The First Affiliated Hospital, School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China; Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering, Hangzhou, 310058, China.
  • 2 College of Pharmaceutical Sciences & Research Center for Clinical Pharmacy, The First Affiliated Hospital, School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China.
  • 3 Zhejiang University of Technology, Hangzhou, 310014, China.
  • 4 Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 5 College of Pharmaceutical Sciences & Research Center for Clinical Pharmacy, The First Affiliated Hospital, School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China. Electronic address: shengr@zju.edu.cn.
  • 6 College of Pharmaceutical Sciences & Research Center for Clinical Pharmacy, The First Affiliated Hospital, School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering, Hangzhou, 310058, China. Electronic address: xmmao@zju.edu.cn.
PMID: 34973507 DOI: 10.1016/j.ejmech.2021.114067
Abstract

Drugs have been largely inspired from Natural Products, while Enzymes underlying their biosynthesis have enabled complex structures and diverse bioactivities. Nevertheless, the high Enzyme specificity and limited in vivo precursor types have restricted the natural product reservoir, but Nature has imprinted Natural Products with active sites, which can be readily modified by chemosynthesis with various functional groups for more favorable druggability. Here in the less exploited fungal Natural Products, we introduced CtvA, a polyketide synthase for a mycotoxin citreoviridin biosynthesis in Aspergillus, into an endophytic fungus Calcarisporium arbuscula to expand tetrahydrofuran (THF) into a dioxabicyclo-octane (DBO) ring moiety based on versatility and promiscuity of the aurovertin biosynthetic Enzyme. Alternative acylations on the hydroxyl groups essential for cell toxicity by chemosynthesis produced compounds with improved anti-tumor activities and pharmacokinetics. Thus, we showed an effective strategic way to optimize the Fungal natural product efficiently for more promising drug development.

Keywords

2,6-dioxabicyclo[3.2.1]-octane; Chemosynthesis; Citreoviridin; Combinatorial biosynthesis; Natural products; Structure expansion.

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