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Molecules 2018, 23(6), 1472; https://doi.org/10.3390/molecules23061472

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

1
Red Sea Research Center, Division of Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
2
Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
3
King Abdullah University of Science and Technology (KAUST), Core Labs, Thuwal 23955-6900, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Received: 21 May 2018 / Revised: 12 June 2018 / Accepted: 15 June 2018 / Published: 18 June 2018
(This article belongs to the Special Issue Biological Potential of Marine and Terrestrial Species)
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Abstract

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. View Full-Text
Keywords: halitoxin; antiviral; Red Sea; bioprospecting; West Nile Virus; NS3 protease; High-Content Screening (HCS) halitoxin; antiviral; Red Sea; bioprospecting; West Nile Virus; NS3 protease; High-Content Screening (HCS)
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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O’Rourke, A.; Kremb, S.; Duggan, B.M.; Sioud, S.; Kharbatia, N.; Raji, M.; Emwas, A.-H.; Gerwick, W.H.; Voolstra, C.R. 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. Molecules 2018, 23, 1472.

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