Identification of a 3-Alkylpyridinium Compound from the Red Sea Sponge Amphimedon chloros with In Vitro Inhibitory Activity against the West Nile Virus NS3 Protease

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2018
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O'Rourke, Aubrie
Kremb, Stephan
Duggan, Brendan M.
Sioud, Salim
Kharbatia, Najeh
Raji, Misjudeen
Emwas, Abdul-Hamid
Gerwick, William H.
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Viruses are underrepresented as targets in pharmacological screening efforts, given the difficulties of devising suitable cell-based and biochemical assays. In this study we found that a pre-fractionated organic extract of the Red Sea sponge Amphimedon chloros was able to inhibit the West Nile Virus NS3 protease (WNV NS3). Using liquid chromatography⁻mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy, the identity of the bioactive compound was determined as a 3-alkylpyridinium with m/z = 190.16. Diffusion Ordered Spectroscopy (DOSY) NMR and NMR relaxation rate analysis suggest that the bioactive compound forms oligomers of up to 35 kDa. We observed that at 9.4 μg/mL there was up to 40⁻70% inhibitory activity on WNV NS3 protease in orthogonal biochemical assays for solid phase extracts (SPE) of A. chloros. However, the LC-MS purified fragment was effective at inhibiting the protease up to 95% at an approximate amount of 2 µg/mL with negligible cytotoxicity to HeLa cells based on a High-Content Screening (HCS) cytological profiling strategy. To date, 3-alkylpyridinium type natural products have not been reported to show antiviral activity since the first characterization of halitoxin, or 3-alkylpyridinium, in 1978. This study provides the first account of a 3-alkylpyridinium complex that exhibits a proposed antiviral activity by inhibiting the NS3 protease. We suggest that the here-described compound can be further modified to increase its stability and tested in a cell-based assay to explore its full potential as a potential novel antiviral capable of inhibiting WNV replication.

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570 Biowissenschaften, Biologie
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halitoxin; antiviral; Red Sea; bioprospecting; West Nile Virus; NS3 protease; High-Content Screening (HCS)
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ISO 690O'ROURKE, Aubrie, Stephan KREMB, Brendan M. DUGGAN, Salim SIOUD, Najeh KHARBATIA, Misjudeen RAJI, Abdul-Hamid EMWAS, William H. GERWICK, Christian R. VOOLSTRA, 2018. Identification of a 3-Alkylpyridinium Compound from the Red Sea Sponge Amphimedon chloros with In Vitro Inhibitory Activity against the West Nile Virus NS3 Protease. In: Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry. Molecular Diversity Preservation International (MDPI). 2018, 23(6), 1472. eISSN 1420-3049. Available under: doi: 10.3390/molecules23061472
BibTex
@article{ORourke2018Ident-51012,
  year={2018},
  doi={10.3390/molecules23061472},
  title={Identification of a 3-Alkylpyridinium Compound from the Red Sea Sponge Amphimedon chloros with In Vitro Inhibitory Activity against the West Nile Virus NS3 Protease},
  number={6},
  volume={23},
  journal={Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry},
  author={O'Rourke, Aubrie and Kremb, Stephan and Duggan, Brendan M. and Sioud, Salim and Kharbatia, Najeh and Raji, Misjudeen and Emwas, Abdul-Hamid and Gerwick, William H. and Voolstra, Christian R.},
  note={Article Number: 1472}
}
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