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Antiviral activity of ethanol extract of Geranii Herba and its components against influenza viruses via neuraminidase inhibition.

ABSTRACT: Influenza viruses are a serious threat to human health, causing numerous deaths and pandemics worldwide. To date, neuraminidase (NA) inhibitors have primarily been used to treat influenza. However, there is a growing need for novel NA inhibitors owing to the emergence of resistant viruses. Geranii Herba (Geranium thunbergii Siebold et Zuccarini), which is edible, has long been used in a variety of disease treatments in Asia. Although recent studies have reported its various pharmacological activities, the effect of Geranii Herba and its components on influenza viruses has not yet been reported. In this study, Geranii Herba ethanol extract (GHE) and its component geraniin showed high antiviral activity against influenza A strain as well as influenza B strain, against which oseltamivir has less efficacy than influenza A strain, by inhibiting NA activity following viral infection in Madin-Darby canine kidney cells. Thus, GHE and its components may be useful for the development of anti-influenza drugs.

SUBMITTER: Choi JG

PROVIDER: S-EPMC6702199 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Antiviral activity of ethanol extract of Geranii Herba and its components against influenza viruses via neuraminidase inhibition.

Choi Jang-Gi JG Kim Young Soo YS Kim Ji Hye JH Chung Hwan-Suck HS

Scientific reports 20190820 1

Influenza viruses are a serious threat to human health, causing numerous deaths and pandemics worldwide. To date, neuraminidase (NA) inhibitors have primarily been used to treat influenza. However, there is a growing need for novel NA inhibitors owing to the emergence of resistant viruses. Geranii Herba (Geranium thunbergii Siebold et Zuccarini), which is edible, has long been used in a variety of disease treatments in Asia. Although recent studies have reported its various pharmacological activ ...[more]

PMID: 31431635

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Project description:Currently, two neuraminidase (NA) inhibitors, oseltamivir and zanamivir, which must be administrated twice daily for 5 days for maximum therapeutic effect, are licensed for the treatment of influenza. However, oseltamivir-resistant mutants of seasonal H1N1 and highly pathogenic H5N1 avian influenza A viruses have emerged. Therefore, alternative antiviral agents are needed. Recently, a new neuraminidase inhibitor, R-125489, and its prodrug, CS-8958, have been developed. CS-8958 functions as a long-acting NA inhibitor in vivo (mice) and is efficacious against seasonal influenza strains following a single intranasal dose. Here, we tested the efficacy of this compound against H5N1 influenza viruses, which have spread across several continents and caused epidemics with high morbidity and mortality. We demonstrated that R-125489 interferes with the NA activity of H5N1 viruses, including oseltamivir-resistant and different clade strains. A single dose of CS-8958 (1,500 microg/kg) given to mice 2 h post-infection with H5N1 influenza viruses produced a higher survival rate than did continuous five-day administration of oseltamivir (50 mg/kg twice daily). Virus titers in lungs and brain were substantially lower in infected mice treated with a single dose of CS-8958 than in those treated with the five-day course of oseltamivir. CS-8958 was also highly efficacious against highly pathogenic H5N1 influenza virus and oseltamivir-resistant variants. A single dose of CS-8958 given seven days prior to virus infection also protected mice against H5N1 virus lethal infection. To evaluate the improved efficacy of CS-8958 over oseltamivir, the binding stability of R-125489 to various subtypes of influenza virus was assessed and compared with that of other NA inhibitors. We found that R-125489 bound to NA more tightly than did any other NA inhibitor tested. Our results indicate that CS-8958 is highly effective for the treatment and prophylaxis of infection with H5N1 influenza viruses, including oseltamivir-resistant mutants.

Project description:The emergence of drug-resistant influenza A virus (IAV) strains represents a serious threat to global human health and underscores the need for novel approaches to anti-influenza chemotherapy. Combination therapy with drugs affecting different IAV targets represents an attractive option for influenza treatment. We have previously shown that the thiazolide anti-infective nitazoxanide (NTZ) inhibits H1N1 IAV replication by selectively blocking viral hemagglutinin maturation. Herein we investigate the anti-influenza activity of NTZ against a wide range of human and avian IAVs (H1N1, H3N2, H5N9, H7N1), including amantadine-resistant and oseltamivir-resistant strains, in vitro. We also investigate whether therapy with NTZ in combination with the neuraminidase inhibitors oseltamivir and zanamivir exerts synergistic, additive, or antagonistic antiviral effects against influenza viruses. NTZ was effective against all IAVs tested, with 50% inhibitory concentrations (IC50s) ranging from 0.9 to 3.2 μM, and selectivity indexes (SIs) ranging from >50 to >160, depending on the strain and the multiplicity of infection (MOI). Combination therapy studies were performed in cell culture-based assays using A/Puerto Rico/8/1934 (H1N1), A/WSN/1933 (H1N1), or avian A/chicken/Italy/9097/1997 (H5N9) IAVs; dose-effect analysis and synergism/antagonism quantification were performed using isobologram analysis according to the Chou-Talalay method. Combination index (CI) analysis indicated that NTZ and oseltamivir combination treatment was synergistic against A/Puerto Rico/8/1934 (H1N1) and A/WSN/1933 (H1N1) IAVs, with CI values ranging between 0.39 and 0.63, independently of the MOI used. Similar results were obtained when NTZ was administered in combination with zanamivir (CI=0.3 to 0.48). NTZ-oseltamivir combination treatment was synergistic also against the avian A/chicken/Italy/9097/1997 (H5N9) IAV (CI=0.18 to 0.31). Taken together, the results suggest that regimens that combine neuraminidase inhibitors and nitazoxanide exert synergistic anti-influenza effects.

Dataset Information

Antiviral activity of ethanol extract of Geranii Herba and its components against influenza viruses via neuraminidase inhibition.

Publications

Antiviral activity of ethanol extract of Geranii Herba and its components against influenza viruses via neuraminidase inhibition.

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