A rise in the level of resistance to current antiviral inhibitors to influenza neuraminidase has prompted a drive to discover potential new drugs to this and other viral protein targets. In large part, however, there has been a disconnect between theoretical studies which model and simulate the binding of potential antiviral drugs to target proteins, and biochemical and cell-based assays of their inhibitory properties which lack any molecular detail.
We have advanced new mass spectrometry approaches, developed and applied in our laboratory over a period of nearly 20 years, to help bridge this divide by providing a relatively rapid, high-throughput and sensitive strategy with which to experimentally screen potential inhibitors against a range of viral target proteins. Importantly, the data provides a more intimate view of the site of binding and potential contact residues not afforded by other assays. We have demonstrated that the approaches enable the relative affinity of various drugs to a common target to be identified, and that these are in accord with their inhibitory constants. Results from these experimental studies are conducted in parallel with rational design and computational docking thereby providing a multi-faceted discovery approach.
Results from several of our recent studies that involve the design and evaluation of new antiviral inhibitors to both influenza hemagglutinin and neuraminidase will be shown. The potential pitfalls of designing new antiviral drugs to influenza, and the impact of resistance mutations in that process, will also be discussed.