Grant: Operating Grant

The development of therapies for treatment of viral diseases has proved to be much more challenging than for bacterial infections. Despite stunning successes such as the AIDS drugs, the development of resistant virus strains has generally required use of combination therapies of two or more drugs. A new therapeutic strategy has recently been developed for influenza, involving a drug that slows a viral enzyme, a sialidase, which cuts a sugar (sialic acid) off the surface of the cell that has been invaded, thereby stopping spread of the virus. The drugs currently available, Tamiflu and Relenza, are now being stockpiled in large quantities by many countries in the face of the very real danger of an influenza pandemic, especially one evolving from avian influenza. Unfortunately, at the same time, strains of influenza virus that are resistant to Tamiflu are now in common circulation. Consequently new influenza therapeutics are urgently needed, preferably incorporating a design that minimizes the probability of development of resistance. Our laboratory has recently uncovered the detailed mechanism by which these enzymes, sialidases, work, and thereby developed and synthesized effective inhibitors of these enzymes that are highly specific for viral enzymes, and do not affect their human counterparts. Since they closely mimic the structure of the natural sialic acid substrate they should be much less likely to induce resistance development. These compounds work as highly effective anti-viral agents against most, but not all, viral strains in cell-based assays. We now propose a series of studies to probe why they show such strain-dependent variability, to see if the compounds work as anti-viral agents in animals (mice), and to design and synthesise even more effective inhibitors based upon what we have learned. We shall also apply a parallel approach to the development of anti-trypanosomal agents for treatment of Chagas disease.