Abstract
Influenza viruses cause significant morbidity and mortality worldwide. Long-term or frequent use of approved anti-influenza agents has resulted in drug-resistant strains, thereby necessitating the discovery of new drugs. In this study, we found aprotinin, a serine protease inhibitor, as an anti-influenza candidate through screening of compound libraries. Aprotinin has been previously reported to show inhibitory effects on a few influenza A virus (IAV) subtypes (e.g., seasonal H1N1 and H3N2). However, because there were no reports of its inhibitory effects on the other types of influenza viruses, we investigated the inhibitory effects of aprotinin in vitro on a wide range of influenza viruses, including avian and oseltamivir-resistant influenza virus strains. Our cell-based assay showed that aprotinin had inhibitory effects on seasonal human IAVs (H1N1 and H3N2 subtypes), avian IAVs (H5N2, H6N5, and H9N2 subtypes), an oseltamivir-resistant IAV, and a currently circulating influenza B virus. We have also confirmed its activity in mice infected with a lethal dose of influenza virus, showing a significant increase in survival rate. Our findings suggest that aprotinin has the capacity to inhibit a wide range of influenza virus subtypes and should be considered for development as a therapeutic agent against influenza.
Highlights
Influenza viruses cause significant morbidity and mortality worldwide
In this study, we investigated the effects of aprotinin on various subtypes of influenza A virus (IAV), including (i) human seasonal IAVs, (ii) avian influenza viruses with zoonotic potential (H5N2, H9N2, and H6N2), (iii) oseltamivir-resistant IAV, and (iv) on a currently circulating strain of influenza B virus (IBV) in vitro
Aprotinin was more effective than oseltamivir at reducing IBV production. These results suggest that aprotinin can significantly reduce the production of oseltamivirresistant IAV and IBV
Summary
Influenza viruses cause significant morbidity and mortality worldwide. Long-term or frequent use of approved anti-influenza agents has resulted in drug-resistant strains, thereby necessitating the discovery of new drugs. Aprotinin has been previously reported to show inhibitory effects on a few influenza A virus (IAV) subtypes (e.g., seasonal H1N1 and H3N2). Our cell-based assay showed that aprotinin had inhibitory effects on seasonal human IAVs (H1N1 and H3N2 subtypes), avian IAVs (H5N2, H6N5, and H9N2 subtypes), an oseltamivir-resistant IAV, and a currently circulating influenza B virus. Current influenza vaccines have several limitations, including their limited efficacy due to antigenic mismatches between the vaccine and circulating virus strains[7] For this reason, antiviral drugs are important for controlling influenza. In this study, we investigated the effects of aprotinin on various subtypes of IAV, including (i) human seasonal IAVs, (ii) avian influenza viruses with zoonotic potential (H5N2, H9N2, and H6N2), (iii) oseltamivir-resistant IAV, and (iv) on a currently circulating strain of IBV in vitro. Our findings contribute further evidence to the potential of aprotinin as a broad-spectrum anti-influenza agent
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