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 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.influenza virus | hemagglutinin | membrane fusion | lectin | antiviral

Human Influenza Virus Hemagglutinins Contain Conserved Oligomannose N-Linked Glycans Allowing Potent Neutralization by Lectins

“…(Lusvarghi and Bewley, 2016) against HIV and influenza infection, the latter of which has recently entered clinical trials (National Institutes of Health, 2019), certainly provides an interesting precedent for adaptation of these lectins for pharmaceutical application. In this regard, a recent report describes an engineered Banlec that exhibits anti-influenza activity in mice and is extremely well tolerated (Cové s-Datson et al, 2020).…”

COVID-19 preclinical models: human angiotensin-converting enzyme 2 transgenic mice

“…In 2006, Tseng at. al, developed the hACE2 Tg mouse lineages (i.e., AC-12, AC-22, AC-50, AC-63, and AC-70) expressing hACE2 under the CAG promoter, a composite promoter consisting of the cytomegalovirus immediate early enhancer, the chicken β-actin promoter, rabbit globulin splicing, and polyadenylation sites to drive high levels of gene expression in eukaryotic expression Mortality (%) The viral dosage used in the study, 2.3 × 10 4 plaque-forming units (PFU), was converted to the estimated TCID50 by the conversion TCID50 ≈ 0.7 PFU [71].…”

“…The viral dosage used in the study, 10 5 PFU, was converted to the estimated TCID50 by the conversion TCID50 ≈ 0.7 PFU [71].…”

Nanoluciferase complementation-based biosensor reveals the importance of N- linked glycosylation of SARS-CoV-2 Spike for viral entry

“…We then utilized plant lectins to target this post-translational modi cation and inhibit the ACE2-RBD interaction and demonstrated its potential as an antiviral using a pseudovirion system. A recent study demonstrated that it was viable to engineer a banana lectin to inhibit in uenza A virus infection in mice while minimizing mitogenic effects associated with lectins 29 . The most potent antiviral lectin identi ed in this study, ConA, may similarly act as a lead candidate to enable the development of a SARS-CoV-2 spike glycan-targeted lectin.…”