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

Autor: Arielle R. Rosenberg, Alexandre Vandeputte, Karin Seron, Yves Rouillé, Muriel Lavie, Priscille Brodin, Jean Dubuisson, Sevser Sahpaz, Véronique Pène, Riadh Ksouri, Céline Rivière, Ramla Sahli, Marie-Emmanuelle Sahuc
Přispěvatelé: Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Institut Charles Viollette (ICV) - EA 7394 (ICV), Université du Littoral Côte d'Opale (ULCO)-Université de Lille-Institut National de la Recherche Agronomique (INRA)-Université d'Artois (UA)-Institut Supérieur d'Agriculture, Laboratoire des plantes aromatiques et médicinales (Faculté des Sciences Mathématiques, Physiques et Naturelles, Tunis) (LPAM), Faculté des Sciences Mathématiques, Physiques et Naturelles de Tunis (FST), Université de Tunis El Manar (UTM)-Université de Tunis El Manar (UTM), Virologie de l'hépatite C (EA 4474), Université Paris Descartes - Paris 5 (UPD5), This work was supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS-18208), the European Community (ERC-STG INTRACELLTB grant 260901), the Agence Nationale de la Recherche (ANR-10-EQPX-04-01), the Fonds Européen de Développement Régional (Feder) (12001407 [D-AL] EquipEx ImagInEx BioMed), and the Région Nord-Pas-de-Calais (convention 12000080), We thank platforms of CUMA (University of Lille 2, J. F. Goossens) and LARMN (University of Lille 2, N. Azaroual) for access to equipment. We are grateful to J. Bukh, C. M. Rice, and T. Wakita for providing essential reagents. We are also grateful to Abderrazak Smaoui (Biotechnology Centre of Borj-Cédria) concerning botanical identification and to Thibaut Vausselin for useful discussions. M.-E.S. is a recipient of a Ph.D. Fellowship provided by the French Government., European Project: 260901,EC:FP7:ERC,ERC-2010-StG_20091118,INTRACELLTB(2010), Université d'Artois (UA)-Institut National de la Recherche Agronomique (INRA)-Université du Littoral Côte d'Opale (ULCO)-Institut Supérieur d'Agriculture-Université de Lille, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Faculté des Sciences Mathématiques, Physiques et Naturelles de Tunis - Faculty of Mathematical, Physical and Natural Sciences of Tunis, Séron, Karin, A Chemical Genomics Approach of Intracellular Mycobacterium tuberculosis Towards Defining Specific Host Pathogen Interactions - INTRACELLTB - - EC:FP7:ERC2010-12-01 - 2015-11-30 - 260901 - VALID
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Journal of Virology
Journal of Virology, American Society for Microbiology, In press, 93 (10), pp.1-15. ⟨10.1128/JVI.02009-18⟩
Journal of Virology, In press, 93 (10), pp.1-15. ⟨10.1128/JVI.02009-18⟩
Journal of Virology, American Society for Microbiology, In press, ⟨10.1128/JVI.02009-18⟩
ISSN: 0022-538X
1098-5514
DOI: 10.1128/JVI.02009-18⟩
Popis: International audience; 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
Databáze: OpenAIRE
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