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

ABSTRACTRecent 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 ofJuncus maritimusLam. 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. Noin vitrotoxicity 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 fromJ. 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.IMPORTANCETens 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 fromJuncus 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.

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Dehydrojuncusol, a Natural Phenanthrene Compound Extracted fromJuncus maritimusIs a New Inhibitor of Hepatitis C Virus Replication

10.1101/469361 ◽

2018 ◽

Cited By ~ 1

Author(s):

Marie-Emmanuelle Sahuc ◽

Ramla Sahli ◽

Céline Rivière ◽

Véronique Pène ◽

Muriel Lavie ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Antiviral Activity ◽

Treatment Failure ◽

Natural Compound ◽

Direct Acting Antivirals ◽

Ns5a Protein ◽

Juncus Maritimus ◽

Resistant Mutants ◽

Direct Acting

AbstractRecent 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, search for new inhibitors and with lower cost of production should be pursued. In this context, crude extract ofJuncus maritimusLam. was shown to exhibit high antiviral activity against HCV in cell culture. Bio-guided fractionation allowed isolating and identifying 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 (EC50= 1.35 µM). This antiviral activity was confirmed with a HCV subgenomic replicon and no effect on HCV pseudoparticle entry was observed. Antiviral activity of dehydrojuncusol was also demonstrated in primary human hepatocytes. Noin vitrotoxicity 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 replication of two frequent daclatasvir resistant mutants (L31M or Y93H in NS5A). Finally, resistant mutants to dehydrojuncusol were obtained and showed that HCV NS5A protein is the target of the molecule. In conclusion, dehydrojuncusol, a natural compound extracted fromJ. maritimus, inhibits infection of different HCV genotypes by targeting NS5A protein and is active against HCV resistant variants frequently found in patients with treatment failure.ImportanceTens 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 the 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 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 replication of replicons harboring resistance mutations to anti-NS5A DAAs used in current therapy. Dehydrojuncusol is a natural compound isolated fromJuncus maritimus, a halophilic plant species very common in the coastlines worldwide. This molecule might serve as a lead for the development of new therapy more accessible to hepatitis C patients in the future.

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Misidentification of recombinant hepatitis C virus leading to treatment failure with direct acting antivirals

Journal of Medical Virology ◽

10.1002/jmv.25035 ◽

2018 ◽

Vol 90 (5) ◽

pp. 994-997

Author(s):

Thomas Mourez ◽

Amandine Decroos ◽

Odile Goria ◽

Hélène Montialoux ◽

Fabienne De Oliveira ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Treatment Failure ◽

Recombinant Hepatitis ◽

Direct Acting Antivirals ◽

Direct Acting

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Recent Advances in Antiviral Therapy for Chronic Hepatitis C

Mediators of Inflammation ◽

10.1155/2016/6841628 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 33

Author(s):

Akihiro Tamori ◽

Masaru Enomoto ◽

Norifumi Kawada

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trials ◽

Chronic Hepatitis ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Treatment Failure ◽

Chronic Infection ◽

Direct Acting Antivirals ◽

The Past ◽

Direct Acting

Hepatitis C virus (HCV) infection is a major worldwide health problem. Chronic infection induces continuous inflammation in the liver, progression of hepatic fibrosis, eventual cirrhosis, and possible hepatocellular carcinoma. Eradication of the virus is one of the most important treatment aims. A number of promising new direct-acting antivirals (DAAs) have been developed over the past 10 years. Due to their increased efficacy, safety, and tolerability, interferon-free oral therapies with DAAs have been approved for patients with HCV, including those with cirrhosis. This review introduces the characteristics and results of recent clinical trials of several DAAs: NS3/4A protease inhibitors, NS5A inhibitors, and NS5B inhibitors. DAA treatment failure and prognosis after DAA therapy are also discussed.

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Detection of drug resistance mutations of hepatitis C virus in patients with failure of the treatment with direct acting antivirals

Journal of microbiology epidemiology immunobiology ◽

10.36233/0372-9311-47 ◽

2021 ◽

Vol 98 (1) ◽

pp. 18-27

Author(s):

D. E. Valutite ◽

A. V. Semenov ◽

Yu. V. Ostankova ◽

K. V. Kozlov ◽

A. G. Borisov ◽

...

Keyword(s):

Drug Resistance ◽

Chronic Hepatitis ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Treatment Failure ◽

Chronic Hepatitis C ◽

Direct Acting Antivirals ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Direct Acting

Background. The development of direct acting antivirals (DAAs) has spurred a revolution in treatment of patients with chronic hepatitis C. However, there are cases showing no response to treatment. In 5% of cases, the viral breakthrough is most likely caused by DAA resistance mutations in the hepatitis C virus genome.The purpose of the study is to detect drug resistance mutations of hepatitis C virus in patients with DAA treatment failure.Materials and methods. The study was performed on plasma samples from 3 patients diagnosed with chronic hepatitis C virus infection and demonstrating DAA virological treatment failure. All isolates had genotype 1b. Drug resistance mutations were detected by using direct sequencing of NS3, NS5A, and NS5B genome regions. The detection technique was developed at the Pasteur Research Institute of Epidemiology and Microbiology.Results. Drug resistance mutations were detected in all cases. By using the Geno2pheno [hcv] 0.92 tool, nucleotide substitutions were detected in different viral genome regions and presumably caused resistance or decreased sensitivity to antivirals both present and absent in the sofosbuvir + daclatasvir combination therapy. Antiviral treatment failure in patients with chronic hepatitis C is caused by drug resistance mutations.Conclusions. The developed technique is efficient for detection of drug resistance mutations in NS3, NS5A, and NS5B regions in cases of virological failure of DAA treatment.

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Potent Antiviral Activities of the Direct-Acting Antivirals ABT-493 and ABT-530 with Three-Day Monotherapy for Hepatitis C Virus Genotype 1 Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02264-15 ◽

2015 ◽

Vol 60 (3) ◽

pp. 1546-1555 ◽

Cited By ~ 30

Author(s):

Eric J. Lawitz ◽

William D. O'Riordan ◽

Armen Asatryan ◽

Bradley L. Freilich ◽

Terry D. Box ◽

...

Keyword(s):

Hepatitis C Virus ◽

Viral Load ◽

Hepatitis C ◽

Antiviral Activity ◽

Genotype 1 ◽

Direct Acting Antivirals ◽

Hcv Genotype ◽

Compensated Cirrhosis ◽

Hcv Genotype 1 ◽

Direct Acting

ABT-493 is a hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor, and ABT-530 is an HCV NS5A inhibitor. These direct-acting antivirals (DAAs) demonstrated potent antiviral activity against major HCV genotypes and high barriers to resistancein vitro. In this open-label dose-ranging trial, antiviral activity and safety were assessed during 3 days of monotherapy with ABT-493 or ABT-530 in treatment-naive adults with HCV genotype 1 infection, with or without compensated cirrhosis. The presence of baseline resistance-associated variants (RAVs) was also evaluated. The mean maximal decreases in HCV RNA levels from baseline were approximately 4 log10IU/ml for all ABT-493 doses ranging from 100 mg to 700 mg and for ABT-530 doses of ≥40 mg. There were no meaningful differences in viral load declines for patients with versus without compensated cirrhosis. Twenty-four (50%) of the baseline samples from patients treated with ABT-493 had RAVs to NS3/4A protease inhibitors. Among 40 patients treated with ABT-530, 6 (15%) carried baseline RAVs to NS5A inhibitors. Viral load declines in patients with single baseline NS5A RAVs were similar to those in patients without RAVs. One patient harbored baseline RAVs at 3 NS5A positions and appeared to have a slightly less robust viral load decline on day 3 of monotherapy. No serious or grade 3 (severe) or higher adverse events and no clinically relevant laboratory abnormalities were observed with either compound. ABT-493 and ABT-530 demonstrated potent antiviral activity and acceptable safety during 3-day monotherapy in patients with HCV genotype 1 infection, with or without compensated cirrhosis. Based on these results, phase II studies assessing the combination of these DAAs for the treatment of chronic HCV infection in patients with or without compensated cirrhosis have been initiated. (This study has been registered at ClinicalTrials.gov under registration no. NCT01995071.)

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