Antiviral activity of a synthesized shikonin ester against influenza A (H1N1) virus and insights into its mechanism

  • Biomed Pharmacother. 2017 Sep;93:636-645. doi: 10.1016/j.biopha.2017.06.076.
Yahan Zhang  1 ,  Hongwei Han  2 ,  Hanyue Qiu  2 ,  Hongyan Lin  2 ,  Lugang Yu  3 ,  Wanzhan Zhu  3 ,  Jinliang Qi  4 ,  Rongwu Yang  2 ,  Yanjun Pang  2 ,  Xiaoming Wang  5 ,  Guihua Lu  6 ,  Yonghua Yang  7
Affiliations
  • 1. State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China; Suzhou Industrial Park Center for Disease Control and Prevention, Suzhou 215000, China.
  • 2. State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China.
  • 3. Suzhou Industrial Park Center for Disease Control and Prevention, Suzhou 215000, China.
  • 4. State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China.
  • 5. State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: [email protected].
  • 7. State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address: [email protected].
PMID: 28688289 DOI: 10.1016/j.biopha.2017.06.076
Abstract

This study aimed to examine the Antiviral effects of shikonin ester ((R)-1-(5, 8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-en-1-yl3-(1H- indol-3-yl) propanoate (PMM-034) against influenza A (H1N1) virus. We investigated PMM-034 anti-H1N1 activity and its effect on Caspase 3 gene expression during cellular Apoptosis after Influenza Virus infection in vitro. Neuraminidase (NA) inhibition was assessed in comparison with oseltamivir in the Influenza Virus standard strains A/PR/8/34 to understand the viral mechanism. MDCK and A549 cells were used to investigate influenza viral Infection and the structure-activity relationship between PMM-034 and NA was evaluated by pharmacophore-based docking modeling. The production of viral protein was tested by western blot. A/PR/8/34 induced cell inhibition but this was reduced by PMM-034 to 16μg/mL and this showed a selective index of 10mM. PMM-034 inhibited NA in a dose dependent manner, similar to oseltamivir inhibition. A sharp decrease in viral nucleocapsid protein mRNA was observed in infected cells after treatment with PMM-034. Apoptosis of infected A459 cells was inhibited by PMM-034 with decreased Caspase 3 levels. ARG 118, ARG 152, ARG 371 and GLU 227 in the binding pocket of NA bound to PMM-034 in the docking model. Taken together, these results suggest PMM-034 shikonin ester blocked H1N1 Infection and might be a potential anti-H1N1 drug.

Keywords
Antiviral agents; Drug discovery; Esters; Influenza virus H1N1 sub-type; Shikonin.
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