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A molecularly engineered antiviral banana lectin inhibits fusion and is efficacious against influenza virus infection in vivo.
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.412 ) Pub Date : 2020-01-13 , DOI: 10.1073/pnas.1915152117
Evelyn M Covés-Datson,Steven R King,Maureen Legendre,Auroni Gupta,Susana M Chan,Emily Gitlin,Vikram V Kulkarni,Jezreel Pantaleón García,Donald F Smee,Elke Lipka,Scott E Evans,E Bart Tarbet,Akira Ono,David M Markovitz

There is a strong need for a new broad-spectrum antiinfluenza therapeutic, as vaccination and existing treatments are only moderately effective. We previously engineered a lectin, H84T banana lectin (H84T), to retain broad-spectrum activity against multiple influenza strains, including pandemic and avian, while largely eliminating the potentially harmful mitogenicity of the parent compound. The amino acid mutation at position 84 from histidine to threonine minimizes the mitogenicity of the wild-type lectin while maintaining antiinfluenza activity in vitro. We now report that in a lethal mouse model H84T is indeed nonmitogenic, and both early and delayed therapeutic administration of H84T intraperitoneally are highly protective, as is H84T administered subcutaneously. Mechanistically, attachment, which we anticipated to be inhibited by H84T, was only somewhat decreased by the lectin. Instead, H84T is internalized into the late endosomal/lysosomal compartment and inhibits virus-endosome fusion. These studies reveal that H84T is efficacious against influenza virus in vivo, and that the loss of mitogenicity seen previously in tissue culture is also seen in vivo, underscoring the potential utility of H84T as a broad-spectrum antiinfluenza agent.
更新日期:2020-01-29

 

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