Dehydrojuncusol, a Natural Phenanthrene Compound Extracted from Juncus maritimus Is a New Inhibitor of Hepatitis C Virus RNA Replication

Marie-Emmanuelle Sahuc (1) , Ramla Sahli (2, 3) , Céline Rivière (2) , Véronique Pène (4) , Muriel Lavie (1) , Alexandre Vandeputte (1) , Priscille Brodin (1) , Arielle R. Rosenberg (4) , Jean Dubuisson (1) , Riadh Ksouri (3) , Yves Rouillé (1) , Sevser Sahpaz (2) , Karin Séron (1)

1 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
2 ICV - Institut Charles Viollette (ICV) - EA 7394
3 LPAM - Laboratoire des plantes aromatiques et médicinales (Faculté des Sciences Mathématiques, Physiques et Naturelles, Tunis)
4 EA 4474 - Virologie de l'hépatite C

Recent emergence of direct-acting antivirals (DAAs) targeting hepatitis C virus (HCV) proteins has considerably enhanced the success of antiviral therapy. However, the appearance of DAA-resistant-associated variants is a cause of treatment failure, and the high cost of DAAs renders the therapy not accessible in countries with inadequate medical infrastructures. Therefore, the search for new inhibitors with a lower cost of production should be pursued. In this context, the crude extract of Juncus maritimus Lam. was shown to exhibit high antiviral activity against HCV in cell culture. Bio-guided fractionation allowed the isolation and identification of the active compound, dehydrojuncusol. A time-of-addition assay showed that dehydrojuncusol significantly inhibited HCV infection when added after virus inoculation of HCV genotype 2a (50% effective concentration [EC50] = 1.35 µM). This antiviral activity was confirmed with an HCV subgenomic replicon, and no effect on HCV pseudoparticle entry was observed. Antiviral activity of dehydrojuncusol was also demonstrated in primary human hepatocytes. No in vitro toxicity was observed at active concentrations. Dehydrojuncusol is also efficient on HCV genotype 3a and can be used in combination with sofosbuvir. Interestingly, dehydrojuncusol was able to inhibit RNA replication of two frequent daclatasvir-resistant mutants (L31M or Y93H in NS5A). Finally, mutants resistant to dehydrojuncusol were obtained and showed that the HCV NS5A protein is the target of the molecule. In conclusion, dehydrojuncusol, a natural compound extracted from J. maritimus, inhibits infection of different HCV genotypes by targeting the NS5A protein and is active against resistant HCV variants frequently found in patients with treatment failure. IMPORTANCE Tens of millions of people are infected with hepatitis C virus (HCV) worldwide. Recently marketed direct-acting antivirals (DAAs) targeting HCV proteins have enhanced the efficacy of treatment. However, due to its high cost, this new therapy is not accessible to the vast majority of infected patients. Furthermore, treatment failures have also been reported due to the appearance of viral resistance. Here, we report on the identification of a new HCV inhibitor, dehydrojuncusol, that targets HCV NS5A and is able to inhibit RNA replication of replicons harboring resistance mutations to anti-NS5A DAAs used in current therapy. Dehydrojuncusol is a natural compound isolated from Juncus maritimus, a halophilic plant species that is very common in coastlines worldwide. This molecule might serve as a lead for the development of a new therapy that is more accessible to hepatitis C patients in the future

Mots clés: antiviral agents; dehydrojuncusol; hepatitis C virus; natural antimicrobial products; phenanthrene; viral replication

Domaines: Sciences du Vivant [q-bio]; Virologie

Marie-Emmanuelle Sahuc, Ramla Sahli, Céline Rivière, Véronique Pène, Muriel Lavie, et al.. Dehydrojuncusol, a Natural Phenanthrene Compound Extracted from Juncus maritimus Is a New Inhibitor of Hepatitis C Virus RNA Replication. Journal of Virology, In press, 93 (10), pp.1-15. ⟨10.1128/JVI.02009-18⟩. ⟨hal-02104447⟩