Exploration of the 150 cavity and the role of serendipity in the discovery of inhibitors of influenza virus A neuraminidase

Influenza pandemics are an ongoing threat for the human population, as the avian influenza viruses H5N1 and H7N9 continue to circulate in the bird population and the chance of avian to human transmission increases. Neuraminidase, a glycoprotein located on the surface of the influenza virus, plays a crucial role in the viral replication process and, hence, has proven to be a useful target enzyme for the treatment of influenza infections. The discovery that certain subtypes of influenza neuraminidase have an additional cavity, the 150 cavity, near the substrate binding site has triggered considerable interest in the design of influenza inhibitors that exploit this feature. Currently available antiviral drugs, neuraminidase inhibitors oseltamivir and zanamivir, were designed using crystal structures predating this discovery by some years. This mini review is aimed at summarizing our group’s efforts, together with related work from other groups, on neuraminidase inhibitors that are designed to exploit both th...