Despite the availability of several drugs to treat influenza virus infection, the pathogen remains a serious threat to human health worldwide. With increasing knowledge of the structure and mechanistic function of the viral neuraminidase, we found potential to develop next-generation neuraminidase inhibitors. We and others have recently reported the discovery of a novel sialosyl sulfonate (1), based on the saturated 2‑deoxy-N-acetylneuraminic acid template, as an inhibitor of influenza virus neuraminidase1,2. This compound, which incorporates a sulfonate group in place of the natural carboxylate group, shows much greater inhibitory potency against influenza virus neuraminidase and in vitro virus infection than the carboxylate congener. It is also more potent than the benchmark unsaturated inhibitor Neu5Ac2en 2.
To further explore this new template, we have introduced modifications in place of the ring hydroxyl group that are designed to tailor the compound to the influenza virus neuraminidase active site. We obtained a compound with nanomolar potency against the neuraminidase activity of a panel of human influenza viruses, as well as against in vitro infection. Potency remained unchanged against a neuraminidase variant resistant to the influenza virus drug oseltamivir carboxylate, while the compound is not inhibitory to the human Neu2 neuraminidase. X-ray diffraction data of the N2 neuraminidase in complex with the compound revealed a binding mechanism similar to the one of the influenza virus drug zanamivir bound to N2, with slightly distinct features. Together, these results expand the chemical space for the design and synthesis of novel, potent influenza virus neuraminidase inhibitors that may lead to improved antiviral therapies.