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Anti-Influenza Virus (H5N1) Activity Screening on the Phloroglucinols from Rhizomes of Dryopteris crassirhizoma.

ABSTRACT: For screening the active phloroglucinols on influenza virus (H5N1) from Dryopteris crassirhizoma NaKai, a database was established including twenty-three phloroglucinols that had been isolated from Dryopteris crassirhizoma. Their inhibitory effect on the neuraminidase (NA) of influenza virus H5N1 was screened by molecular docking. As a result, three candidates were selected. The rhizomes of D. crassirhizoma were subjected to isolation and purification processes to obtain the inhibitor candidates. Thirteen phloroglucinols were obtained, including three selected candidates and two new phloroglucinols. The five phloroglucinols were investigated for their inhibitory activity on NA in vitro. The results showed that dryocrassin ABBA and filixic acid ABA exhibited inhibitory effects on NA with IC50 as 18.59 ± 4.53 and 29.57 ± 2.48 ?M, respectively, and the other three phloroglucinols showed moderate inhibitory activity. Moreover, the anti-influenza virus (H5N1) activity and cytotoxicity of dryocrassin ABBA and filixic acid ABA were tested on Madin-Darby canine kidney (MDCK) cells with the cell counting kit-8 (CCK8) method. The results confirmed that dryocrassin ABBA exhibited an inhibitory activity with low cytotoxicity (TC50 > 400 ?M) against influenza virus (H5N1) which will have to be investigated in further detail. In conclusion, phloroglucinols from D. crassirhizoma were shown to have anti-influenza virus activity, and especially dryocrassin ABBA, one of the phloroglucinols, may have the potential to control influenza virus (H5N1) infection.

SUBMITTER: Wang J

PROVIDER: S-EPMC6155227 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Anti-Influenza Virus (H5N1) Activity Screening on the Phloroglucinols from Rhizomes of Dryopteris crassirhizoma.

Wang Juan J Yan Yan-Tao YT Fu Shen-Zhen SZ Peng Bing B Bao Lin-Lin LL Zhang Yan-Ling YL Hu Jing-Hong JH Zeng Zu-Ping ZP Geng Dong-Hao DH Gao Zeng-Ping ZP

Molecules (Basel, Switzerland) 20170308 3

For screening the active phloroglucinols on influenza virus (H5N1) from Dryopteris crassirhizoma NaKai, a database was established including twenty-three phloroglucinols that had been isolated from Dryopteris crassirhizoma. Their inhibitory effect on the neuraminidase (NA) of influenza virus H5N1 was screened by molecular docking. As a result, three candidates were selected. The rhizomes of D. crassirhizoma were subjected to isolation and purification processes to obtain the ...[more]

PMID: 28282885

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Project description:Platelets are an important component of the initial response to vascular endothelial injury; however, platelet dysfunction induces the acute clinical symptoms of thrombotic disorders, which trigger severe cardiovascular diseases such as myocardial infarction, ischemia, and stroke. In this study, we investigated the Dryopteris crassirhizoma's antiplatelet activity. A water extract of D.crassirhizoma (WDC) was partitioned into dichloromethane (DCM), ethyl acetate, n-butyl alcohol, and water. Among these four fractions, the DCM fraction potently inhibited the collagen-stimulated platelet aggregation in a concentration-dependent manner. From this fraction, five different acylphloroglucinol compounds and one flavonoid were isolated by activity-guided column chromatography. They were identified by comparing their mass, 1H-, and 13C-NMR spectral data with those reported in the literature. Quantifying the six compounds in WDC and its DCM fraction by high-performance liquid chromatography (HPLC) revealed that butyryl-3-methylphloroglucinol (compound 4) was the most abundant in these samples. Additionally, butyryl-3-methylphloroglucinol showed the strongest inhibitory activity in the collagen- and arachidonic acid (AA)-induced platelet aggregation, with inhibition ratios of 92.36% and 89.51% in the collagen and AA-induced platelet aggregation, respectively, without cytotoxicity. On the active concentrations, butyryl-3-methylphloroglucinol significantly suppressed the convulxin-induced platelet activation. Regarding the structure-activity relationships for the five acylphloroglucinol compounds, our results demonstrated that the functional butanonyl, methoxy, and hydroxy groups in butyryl-3-methylphloroglucinol play important roles in antiplatelet activity. The findings indicate that acylphloroglucinols, including butyryl-3-methylphloroglucinol from D.crassirhizom, possess an antiplatelet activity, supporting the use of this species for antiplatelet remedies.

Project description:UnlabelledHighly pathogenic H5N1 avian influenza viruses are associated with severe disease in humans and continue to be a pandemic threat. While vaccines are available, other approaches are required for patients that typically respond poorly to vaccination, such as the elderly and the immunocompromised. To produce a therapeutic agent that is highly efficacious at low doses and is broadly specific against antigenically drifted H5N1 influenza viruses, we developed two neutralizing monoclonal antibodies and combined them into a single bispecific Fc fusion protein (the Fc dual-affinity retargeting [FcDART] molecule). In mice, a single therapeutic or prophylactic dose of either monoclonal antibody at 2.5 mg/kg of body weight provided 100% protection against challenge with A/Vietnam/1203/04 (H5N1) or the antigenically drifted strain A/Whooper swan/Mongolia/244/05 (H5N1). In ferrets, a single 1-mg/kg prophylactic dose provided 100% protection against A/Vietnam/1203/04 challenge. FcDART was also effective, as a single 2.5-mg/kg therapeutic or prophylactic dose in mice provided 100% protection against A/Vietnam/1203/04 challenge. Antibodies bound to conformational epitopes in antigenic sites on the globular head of the hemagglutinin protein, on the basis of analysis of mutants with antibody escape mutations. While it was possible to generate escape mutants in vitro, they were neutralized by the antibodies in vivo, as mice infected with escape mutants were 100% protected after only a single therapeutic dose of the antibody used to generate the escape mutant in vitro. In summary, we have combined the antigen specificities of two highly efficacious anti-H5N1 influenza virus antibodies into a bispecific FcDART molecule, which represents a strategy to produce broadly neutralizing antibodies that are effective against antigenically diverse influenza viruses.ImportanceHighly pathogenic H5N1 avian influenza viruses are associated with severe disease in humans and are a pandemic threat. A vaccine is available, but other approaches are required for patients that typically respond poorly to vaccination, such as the elderly and the immunocompromised. The variability of the virus means that such an approach must be broad spectrum. To achieve this, we developed two antibodies that neutralize H5N1 influenza viruses. In mice, these antibodies provided complete protection against a spectrum of H5N1 influenza viruses at a single low dose. We then combined the two antibodies into a single molecule, FcDART, which combined the broad-spectrum activity and protective efficacy of both antibodies. This treatment provides a novel and effective therapeutic agent or prophylactic with activity against highly pathogenic H5N1 avian influenza viruses.

Dataset Information

Anti-Influenza Virus (H5N1) Activity Screening on the Phloroglucinols from Rhizomes of Dryopteris crassirhizoma.

Publications

Anti-Influenza Virus (H5N1) Activity Screening on the Phloroglucinols from Rhizomes of Dryopteris crassirhizoma.

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