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Effects of protease inhibitors on replication of various myxoviruses
M Hosoya1, S Matsuyama, M Baba
1Department of Microbiology, Fukushima Medical College, Japan.
Abstract:
We studied the effects of eight protease inhibitors on the multicycle replications of various orthomyxoviruses and paramyxoviruses. Among the compounds, nafamostat mesilate, camostat mesilate, gabexate mesilate, and aprotinin, which are widely used in the treatment of pancreatitis, inhibited influenza virus A and B replication at concentrations that were significantly lower than their cytotoxic thresholds in vitro. None of the protease inhibitors had activity against respiratory syncytial virus, measles virus, or parainfluenza virus type 3 at the highest concentrations tested. Camostat mesilate was found to be the most selective inhibitor. Its 50% effective concentration for influenza virus A replication was 2.2 micrograms/ml, and the selectivity index, which was based on the ratio of the 50% inhibitory concentration for host cell proliferation to the 50% effective concentration for influenza virus A replication, was 680. When the in ovo antiviral activity of the compounds was tested by using chicken embryos, camostat mesilate at a dose of 10 micrograms/g markedly reduced the hemagglutinin titers of influenza viruses A and B.
Insights
Certain protease inhibitors, like camostat mesilate, effectively inhibit influenza virus replication in vitro and in ovo. These compounds show promise as antiviral agents against influenza, with minimal toxicity.
Area of Science:
- Virology
- Biochemistry
- Pharmacology
Background:
- Orthomyxoviruses and paramyxoviruses cause significant respiratory illnesses.
- Protease inhibitors are used clinically for conditions like pancreatitis.
- Investigating existing drugs for novel antiviral applications is crucial.
Purpose of the Study:
- To evaluate the efficacy of eight protease inhibitors against orthomyxoviruses and paramyxoviruses.
- To identify selective inhibitors of influenza virus replication.
- To assess antiviral activity in both in vitro and in ovo models.
Main Methods:
- In vitro multicycle replication assays were performed for various viruses.
- Cytotoxicity thresholds and 50% effective concentrations (EC50) were determined.
- In ovo antiviral activity was assessed using chicken embryos and hemagglutinin titers.
Main Results:
- Nafamostat mesilate, camostat mesilate, gabexate mesilate, and aprotinin inhibited influenza A and B replication in vitro.
- No tested protease inhibitors showed activity against respiratory syncytial virus, measles virus, or parainfluenza virus type 3.
- Camostat mesilate demonstrated high selectivity (selectivity index of 680) and reduced viral hemagglutinin titers in ovo.
Conclusions:
- Camostat mesilate is a potent and selective inhibitor of influenza virus replication.
- Protease inhibitors, particularly camostat mesilate, represent potential therapeutic candidates for influenza infections.
- Further research into protease inhibitors for viral infections is warranted.