Biology subjects

Seron, K.

Publications and source records attributed to Seron, K..

5 recordsLinked to original sources

bioRxiv2024

MAJOR METABOLITES FROM HYPERICUM PERFORATUM L., HYPERFORIN AND HYPERICIN, ARE BOTH ACTIVE AGAINST HUMAN CORONAVIRUSES

COVID-19 pandemic has highlighted the need of antiviral molecules against coronaviruses. Plants are an endless source of active compounds. In the current study, we investigated the potential antiviral effects of Hypericum perforatum L.. Its extract contained two major metabolites belonging to distinct chemical classes, hypericin (HC) and hyperforin (HF). First, we demonstrated that HC inhibited HCoV-229E at the entry step by directly targeting the viral particle in a light-dependent manner. While antiviral properties have already been described for HC, the study here showed for the first time that HF has pan-coronavirus antiviral capacity. Indeed, HF was highly active against Alphacoronavirus HCoV-229E (IC50 value of 1.10 {micro}M), and Betacoronaviruses SARS-CoV-2 (IC50 value of of 0.24 to 0.98 {micro}M), SARS-CoV (IC50 value of 1.01 {micro}M) and MERS-CoV (IC50 value of 2.55 {micro}M). Unlike HC, HF was active at a post-entry step, most likely the replication step. Antiviral activity of HF on HCoV-229E and SARS-CoV-2 was confirmed in primary human respiratory epithelial cells. Furthermore, in vitro combination assay of HF with remdesivir showed that their association was additive, which was encouraging for a potential therapeutical association. As HF was active on both Alpha- and Betacoronaviruses, a cellular target was hypothesized. Heme oxygenase 1 (HO-1) pathway, a potential target of HF, has been investigated but the results showed that HF antiviral activity against HCoV-229E was not dependent on HO-1. Collectively, HF is a promising antiviral candidate in view of our results and pharmacokinetics studies already published in animal models or in human.

microbiology↗

bioRxiv2021

A photoactivable natural product with broad antiviral activity against enveloped viruses including highly pathogenic coronaviruses

The SARS-CoV-2 outbreak has highlighted the need for broad-spectrum antivirals against coronaviruses (CoVs). Here, pheophorbide a (Pba) was identified as a highly active antiviral molecule against HCoV-229E after bioguided fractionation of plant extracts. The antiviral activity of Pba was subsequently shown for SARS-CoV-2 and MERS-CoV, and its mechanism of action was further assessed, showing that Pba is an inhibitor of coronavirus entry by directly targeting the viral particle. Interestingly, the antiviral activity of Pba depends on light exposure, and Pba was shown to inhibit virus-cell fusion by stiffening the viral membrane as demonstrated by cryo-electron microscopy. Moreover, Pba was shown to be broadly active against several other enveloped viruses, and reduced SARS-CoV-2 and MERS-CoV replication in primary human bronchial epithelial cells. Pba is the first described natural antiviral against SARS-CoV-2 with direct photosensitive virucidal activity that holds potential for COVID-19 therapy or disinfection of SARS-CoV-2 contaminated surfaces.

microbiology↗

bioRxiv2021

Large scale screening discovers clofoctol as an inhibitor of SARS-CoV-2 replication that reduces COVID-19-like pathology

Drug repurposing has the advantage of shortening regulatory preclinical development steps. Here, we screened a library of drug compounds, already registered in one or several geographical areas, to identify those exhibiting antiviral activity against SARS-CoV-2 with relevant potency. Of the 1,942 compounds tested, 21 exhibited a substantial antiviral activity in Vero-81 cells. Among them, clofoctol, an antibacterial drug used for the treatment of bacterial respiratory tract infections, was further investigated due to favorable safety profile and pharmacokinetic properties. Notably, the peak concentration of clofoctol that can be achieved in human lungs is more than 20 times higher than its IC50 measured against SARS-CoV-2 in human pulmonary cells. This compound inhibits SARS-CoV-2 at a post-entry step. Lastly, therapeutic treatment of human ACE2 receptor transgenic mice decreased viral load, reduced inflammatory gene expression and lowered pulmonary pathology. Altogether, these data strongly support clofoctol as a therapeutic candidate for the treatment of COVID-19 patients. SummaryAntivirals targeting SARS-CoV-2 are sorely needed. In this study, we screened a library of drug compounds and identified clofoctol as an antiviral against SARS-CoV-2. We further demonstrated that, in vivo, this compound reduces inflammatory gene expression and lowers pulmonary pathology.

microbiology↗

bioRxiv2018

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

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, search for new inhibitors and with lower cost of production should be pursued. In this context, crude extract of Juncus maritimus Lam. 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 {micro}M). 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. 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 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 from J. 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.\n\nImportanceTens 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 \nDAAs used in current therapy. Dehydrojuncusol is a natural compound isolated from Juncus 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.

microbiology↗

bioRxiv2018

Theaflavins, polyphenols of black tea, inhibit entry of hepatitis C virus

The treatment of hepatitis C virus (HCV) infection by combination of direct acting antivirals (DAA), with different mode of action, has made substantial progress in the past few years. However, appearance of resistance and high cost of the therapy is still an obstacle in the achievement of the therapy, more specifically in developing countries. In this context, search for affordable antivirals with new mechanisms of action is still needed. Tea, after water, is the most popular drink worldwide. Polyphenols extracted from green tea have already shown anti-HCV activity as entry inhibitors. Here, three different theaflavins, theaflavin (TF1), theaflavin-3-monogallate (TF2), and theaflavin-3-3-digallate (TF3), which are major polyphenols from black tea, were tested against HCV in cell culture. The results showed that all theaflavins inhibit HCV infection in a dose-dependent manner in an early step of infection. Results obtained with HCV pseudotyped virions confirmed their activity on HCV entry and demonstrated their pan-genotypic action. No effect on HCV replication was observed by using HCV replicon. Investigation on the mechanism of action of black tea theaflavins showed that they act directly on the virus particle and are able to inhibit cell-to-cell spread. Combination study with inhibitors most widely used in anti-HCV treatment regimen demonstrated that TF3 exerts additive effect. In conclusion, theaflavins, that are present in high quantity in black tea, are new inhibitors of HCV entry and hold promise for developing in therapeutic arsenal for HCV infection.

microbiology↗