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Proc Natl Acad Sci U S A. 2020 Jan 13. pii: 201915152. doi: 10.1073/pnas.1915152117. [Epub ahead of print] A molecularly engineered antiviral banana lectin inhibits fusion and is efficacious against influenza virus infection in vivo.
Cov?s-Datson EM1,2, King SR3,4, Legendre M3, Gupta A3, Chan SM4,5, Gitlin E3, Kulkarni VV6, Pantale?n Garc?a J6, Smee DF7, Lipka E4, Evans SE6, Tarbet EB7, Ono A2, Markovitz DM8,5,9,10.
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Abstract
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.
Copyright ? 2020 the Author(s). Published by PNAS.
KEYWORDS:
antiviral; hemagglutinin; influenza virus; lectin; membrane fusion
PMID: 31932446 DOI: 10.1073/pnas.1915152117