2. Academic Validation
  3. Targeted discovery of diterpene compounds ostamycins with anti-influenza a viral activity from a deepsea-derived Streptomyces strain

Targeted discovery of diterpene compounds ostamycins with anti-influenza a viral activity from a deepsea-derived Streptomyces strain

  • Bioorg Chem. 2025 Apr:157:108268. doi: 10.1016/j.bioorg.2025.108268.
Lukuan Hou 1,  Shuyao Wang 2,  Yuanhang Zhang 3,  Xue Yang 4,  Zihui Chen 5,  Yuxuan Gao 6,  Wenli Li 7
Affiliations

Affiliations

  • 1 State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shannxi 712100, China. Electronic address: houlukuan@nwafu.edu.cn.
  • 2 State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shannxi 712100, China. Electronic address: shuyaowang@nwafu.edu.cn.
  • 3 State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shannxi 712100, China. Electronic address: zyhfromhnyz@nwafu.edu.cn.
  • 4 State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shannxi 712100, China. Electronic address: YangXue111@nwafu.edu.cn.
  • 5 School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-Lane Xiangshan, Hangzhou 310024, China. Electronic address: chenzihui@ucas.ac.cn.
  • 6 State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shannxi 712100, China. Electronic address: nikoafk5323@gmail.com.
  • 7 State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shannxi 712100, China. Electronic address: liwenli@nwafu.edu.cn.
PMID: 39986106 DOI: 10.1016/j.bioorg.2025.108268
Abstract

Heterologous expression of a nonconventional terpene biosynthetic gene cluster from the deepsea-derived Streptomyces amphotericinicus DS22-01 led to the production of a novel cyclic diterpene, ostamycin A (1). Anti-influenza A virus activity evaluation revealed that compound 1 showed significant activity with an IC50 value of 4.72 μM, which was much stronger than that of the positive control ribavirin (IC50 = 20.80 μM). Inspired by its intriguing activity, yield optimization was achieved through a combined approach involving promoter engineering and codon modification in a stepwise manner. This strategy led to a ∼ 13-fold increase in the production of ostamycin A (1), as well as the concurrent accumulation of another novel cyclic diterpene, ostamycin B (2), which also displayed anti-influenza A virus activity with an IC50 value of 195.59 μM. The planar structures and stereochemistry of compounds 1 and 2 were established through extensive MS and NMR spectroscopic analyses together with ECD calculations. Further investigations revealed that compound 1 inhibits the influenza A virus (A/Puerto Rico/8/34) replication by directly targeting the nucleoprotein (NP). These findings highlight compound 1 as a promising lead for the development of novel Influenza Virus inhibitors.

Keywords

Antiviral; Atypical diterpene cyclases; Deepsea-derived Streptomyces; Diterpene; Nucleoprotein.

Figures
Products