A small-molecule fusion inhibitor of influenza virus is orally active in mice.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30846569.
- Also identified by DOI 10.1126/science.aar6221 and PMC identifier 6457909.
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Abstract
Recent characterization of broadly neutralizing antibodies (bnAbs) against influenza virus identified the conserved hemagglutinin (HA) stem as a target for development of universal vaccines and therapeutics. Although several stem bnAbs are being evaluated in clinical trials, antibodies are generally unsuited for oral delivery. Guided by structural knowledge of the interactions and mechanism of anti-stem bnAb CR6261, we selected and optimized small molecules that mimic the bnAb functionality. Our lead compound neutralizes influenza A group 1 viruses by inhibiting HA-mediated fusion in vitro, protects mice against lethal and sublethal influenza challenge after oral administration, and effectively neutralizes virus infection in reconstituted three-dimensional cell culture of fully differentiated human bronchial epithelial cells. Cocrystal structures with H1 and H5 HAs reveal that the lead compound recapitulates the bnAb hotspot interactions.
Medical subject headings
- Antibodies, Neutralizing
- Biomimetic Materials
- Influenza A Virus, H1N1 Subtype
- Influenza, Human
- Piperazines
- Pyridines
- Tetrazoles
- Viral Fusion Protein Inhibitors
- Virus Internalization