1. A molecularly engineered antiviral banana lectin inhibits fusion and is efficacious against influenza virus infection in vivo
- Author
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Vikram V. Kulkarni, Steven R. King, Scott E. Evans, Emily Gitlin, Susana M. Chan, David M. Markovitz, E. Bart Tarbet, Maureen Legendre, Elke Lipka, Donald F. Smee, Jezreel Pantaleón García, Auroni Gupta, Akira Ono, Evelyn M. Covés-Datson, and National Academy of Sciences
- Subjects
Male ,0301 basic medicine ,membrane fusion ,030106 microbiology ,Hemagglutinin (influenza) ,Dairy Science ,Protein Engineering ,Microbiology ,Antiviral Agents ,influenza virus ,Virus ,Mice ,03 medical and health sciences ,Tissue culture ,Influenza A Virus, H1N1 Subtype ,In vivo ,Lectins ,Influenza, Human ,Animals ,Humans ,hemagglutinin ,Threonine ,Plant Proteins ,Multidisciplinary ,biology ,Influenza A Virus, H3N2 Subtype ,Lectin ,Lipid bilayer fusion ,Musa ,Biological Sciences ,Virus Internalization ,antiviral ,Virology ,In vitro ,3. Good health ,030104 developmental biology ,Animal Sciences ,Mutation ,biology.protein ,lectin - Abstract
Significance There is a pressing need for new antiinfluenza therapeutic agents. We show that a molecularly engineered banana lectin (carbohydrate-binding protein) has broad-spectrum activity against all influenza strains tested, including drug-resistant and currently circulating strains; is safe upon repeated administration in mice; and, moreover, is efficacious at treating lethal influenza infection via clinically pertinent routes of administration. We demonstrate that the lectin binds to the viral hemagglutinin glycoprotein and exerts its primary antiviral effect via inhibition of an early stage of the viral life cycle, viral membrane fusion to the host endosomal membrane. Our findings indicate that this engineered lectin, which has a mechanism of action quite distinct from the presently available agents, has potential as an antiinfluenza agent., 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.
- Published
- 2020