Novel Rigid Glycomimetics to Inhibit Influenza Infection

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Small‐molecule anti‐influenza agents, such as zanamivir and oseltamivir are neuraminidase (NA) inhibitors limit the release of progeny virions from infected cells through competitive binding to the viral NA. However, these drugs do not block infection. Vaccination is the most common approach for preventing influenza infection, but vaccine creation takes approximately 6 months and requires prior knowledge of the circulating virus strains. The impact of this limitation was evident in the 2009 swine flu pandemic, against which the seasonal vaccine was completely ineffective. The urgent need to develop complementary strategies to vaccination or NA inhibition is emphasized by the fact that between 2006 and 2009 seasonal flu developed almost complete resistance to oseltamivir, resulting from a single spontaneous mutation in the viral NA.As a potential alternative to current flu antivirals, we are developing glycomimetics that block the interaction between the viral hemagglutinin (HA) and the host glycans that serve as flu‐receptors. This interaction is essential for viral adhesion, and the universal receptor for flu A [15] and B [16] viruses is Sia‐Gal (sialic acid, Sia, a.k.a. neuraminic acid, linked to galactose, Gal). HAs from either human (H1N1) or avian‐infective (N5N1) flu strains bind to di‐ or trisaccharides terminating in Sia‐Gal regardless of whether the Sia‐Gal linkage is α2,6 or α2,3. This observation suggested that a small Sia‐Gal glycomimetic might be developed that could inhibit a broad range of flu A strains, including flu B, and was critical in the design of our glycomimetic framework (FB127).Here were report that FB127 shows dose‐dependent inhibition of the infection of MDCK cells by a range of flu viruses from group 1 (H1N1, H5N1), group 2 (H3N2), and flu B, and that the influenza neutralizing ability of FB127 is within the same range as reported for glycodendrimers. Because FB127 is a synthetic small molecule, it can be rationally modified, and manufactured with a high degree of quality control and reproducibility. In this regard, FB127 is amenable to a number of formulations, including aerosol, oral, and intravenous routes that provide great flexibility in drug delivery.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.