@article{edf4a2e8941d47c3b5cd256c5b78e27a,
title = "A molecularly engineered antiviral banana lectin inhibits fusion and is efficacious against influenza virus infection in vivo",
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 7administration 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.",
keywords = "Antiviral, Hemagglutinin, Influenza virus, Lectin, Membrane fusion",
author = "Cov{\'e}s-Datson, {Evelyn M.} and King, {Steven R.} and Maureen Legendre and Auroni Gupta and Chan, {Susana M.} and Emily Gitlin and Kulkarni, {Vikram V.} and Garc{\'i}a, {Jezreel Pantale{\'o}n} and Smee, {Donald F.} and Elke Lipka and Evans, {Scott E.} and Tarbet, {E. Bart} and Akira Ono and Markovitz, {David M.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank A. Krafft and the Influenza Drug Development and Diagnostic Development Program at the National Institute of Allergy and Infectious Diseases for support for testing of H84T against influenza virus in vitro and in vivo; S. Bedi from the University of Michigan for providing supernatants from influenza plasmid-transfected cells for virus propagation; S. Hensley from the University of Pennsylvania for providing H17-L19 antibody and 3C.2a virus; S. Yalavarthi and J. Knight from the University of Michigan for providing human donor sera; and E. Martens from the University of Michigan for providing galactose and yeast mannan. This work was supported by grants to D.M.M. from the Defense Threat Reduction Agency (HDTRA1-15-1-0067) and the University of Michigan MTRAC (Michigan Translational Research and Commercialization Life Sciences). E.M.C.-D. was supported by training grants from the University of Michigan Medical Scientist Training Program (T32 GM07863) and the Molecular Mechanisms of Microbial Pathogenesis Training Program (T32 AI007528) from the National Institutes of Health, and by a National Research Service Award (1F31AI136615-01) from the National Institute of Allergy and Infectious Diseases. Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = jan,
day = "28",
doi = "10.1073/pnas.1915152117",
language = "English (US)",
volume = "117",
pages = "2122--2132",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "4",
}