2. Academic Validation
  3. Generation of methylated violapyrones with improved anti-influenza A virus activity by heterologous expression of a type III PKS gene in a marine Streptomyces strain

Generation of methylated violapyrones with improved anti-influenza A virus activity by heterologous expression of a type III PKS gene in a marine Streptomyces strain

  • Bioorg Med Chem Lett. 2018 Sep 15;28(17):2865-2868. doi: 10.1016/j.bmcl.2018.07.029.
Lukuan Hou 1,  Shuyao Wang 1,  Huiming Huang 1,  Huayue Li 2,  Wei Wang 3,  Wenli Li 4
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
  • 2 Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266273, China. Electronic address: lihuayue@ouc.edu.cn.
  • 3 Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266273, China. Electronic address: wwwakin@ouc.edu.cn.
  • 4 Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266273, China. Electronic address: liwenli@ouc.edu.cn.
PMID: 30033162 DOI: 10.1016/j.bmcl.2018.07.029
Abstract

Heterologous expression of the type III polyketide synthase (PKS) gene vioA in marine-derived Streptomyces youssoufiensis OUC6819 led to production of six violapyrones (VLPs), including four novel compounds VLPs Q-T (1-4) and two known compounds VLPs B and I (5 and 6). The structures of 1-4 were elucidated by a combination of spectroscopic analyses, including HR-ESIMS and 1D and 2D NMR data, demonstrating that 1-4 are novel VLPs which are methylated at 4-OH with their corresponding non-methylated counterparts to be VLP A, 5 and 6 and VLP C, respectively. Anti-influenza A [H1N1 (A/Virginia/ATCC1/2009) and H3N2 (A/Aichi/2/1968)] virus activity of compounds 1-6 as well as VLPs A and C were then evaluated using ribavirin as a positive control (IC50 = 66.7 and 99.6 μM). The results revealed that these VLPs showed considerable anti-H1N1 and anti-H3N2 activities with IC50 values of 30.6-132.4 μM and 45.3-150.0 μM, respectively. Notably, all the methylated VLPs displayed better anti-virus activity than their non-methylated counterparts, among which compound 3 (VLP S) exhibited the best activities. Interestingly, methylation at 4-OH has negative effect on the anti-MRSA (methicillin-resistant Staphylococcus aureus) activity instead, with methylated VLPs displaying decreased (2) or abolished (3 and 4) activities in comparison with each of their non-methylated counterparts.

Keywords

Anti-MRSA; Anti-influenza A; Heterologous expression; Streptomyces; Violapyrones (VLPs).

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