Dual-acting compounds that deliver an acidifying domain via zanamivir to the virus surface are potent influenza inhibitors

Contemporary antiviral development, whether by rational drug design or forward pharmacology, primarily strives to produce ‘lock and key’ inhibitors. While the technology to identify druggable targets and create compounds to bind them has improved dramatically over the last century it has always been constrained by the finite availability of suitable binding sites that antiviral compounds can occupy. Here we present a new approach to drug design that utilizes compounds devised to alter the microenvironment of the virion surface making it incompatible with virus entry and illustrate this strategy with inhibitors of influenza virus. We show that compounds that produce a proton-rich mantle above the virion surface induce a conformational change in the viral hemagglutinin (HA) rendering the virus unable to interact with cellular receptors and gain entry to the cell. The compounds show exceptional antiviral activity both in vitro and in vivo and protect against influenza illness in mice and ferrets after a single dose, either therapeutically or prophylactically. The work presented here lays the foundation for a brand-new category of inhibitors that could be engineered to counter many different viruses and potentially other pathogens.