A new inhibitor of hepatitis C virus replication from Juncus maritimus, a Tunisian extremophile plant

Hepatitis C virus (HCV) infection is a major cause of chronic liver diseases. A new generation of anti-HCV drugs (viral protein inhibitors) with a superior efficacy and a better safety profile is currently available. However, they are very expensive and not accessible in developing countries. Also, the emergence of resistant HCV variants continues to be a public health issue [1]. The discovery of new HCV inhibitors remains necessary to lower the cost of treatment and deepen the understanding of HCV life cycle.

In this context, several crude methanolic extracts of extremophile plants from Tunisia were screened against HCV in cell culture. Infection and replication rates in Huh-7 hepatoma cells were investigated by indirect immunofluorescence assay. The rhizome's crude extract of Juncus maritimus Lam., a halophyte plant belonging to Juncaceae family, exhibited the highest activity, especially against HCV replication (relative infection < 10% at 25 µg/mL). Bioguided fractionation showed that the methylene chloride partition was most likely responsible for this activity (relative infection = 6.26% at 25 µg/mL). From this partition, several compounds were isolated by CPC and preparative HPLC and then tested against HCV. One of these compounds, dehydrojuncusol, a known phenanthrene derivative [2], identified by HR-MS and NMR, was the most active.

Compared to DMSO-treated cells, dehydrojuncusol significantly inhibited HCV infection when added during the inoculation step (IC₅₀ = 5.56µM), and even more when added during the post-inoculation (replication) step (IC₅₀= 1.31µM). Its effect against HCV replication was similar to boceprevir (0.5µM), an inhibitor of the viral polymerase used as positive control. Moreover, it showed no in vitro toxicity on Huh-7 cells at active concentrations. Few natural products have demonstrated activity on viral replication of HCV [3]. Activity assays against HCV resistant mutants are underway to help us understanding the dehydrojuncusol mechanism of action.

* Both authors contributed equally to this work.

Acknowledgements: The authors wish to thank CUMA (Pr. J.F. Goossens) and LARMN (Pr. N. Azaroual) from University of Lille 2 (France) for access to equipment and the members of these platforms for their skillfull technical assistant.

Keywords: phenanthrene, Juncus maritimus, antiviral activity, HCV, extremophile plants.

References:

[1] Galani BRT, Sahuc ME, Sass G, Njayou FN, Loscher C, Mkounga P, Deloison G, Brodin P, Rouillé Y, Tiegs G, Seron K, Moundipa PF. Khaya grandifoliola C.DC: a potential source of active ingredients against hepatitis C virus in vitro. Arch Virol 2016; 161: 1169 – 1181

[2] Sarkar H, Zerezchi M, Bhattacharyya J. Dehydrojuncusol, a constituent of the roots of Juncus roemerianus. Phytochemistry 1988; 27: 3006 – 3008

[3] Calland N, Dubuisson J, Rouillé Y, Séron K. Hepatitis C virus and natural compounds: a new antiviral approach? Viruses 2012; 10: 2197 – 2217

 

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