Influenza causes 10,000-20,000 deaths every winter in the U.S. Current preventive measures include vaccines and antiviral drugs. Vaccines are not effective during a major antigenic variation of influenza, and the only licensed anti-influenza drugs, amantadine and rimantidine, act only against influenza A which quickly becomes resistant. The death rate from influenza and pneumonia continues to increase. New drugs which the virus cannot easily evade by mutation are needed. Neuraminidase (NA) is a surface enzyme on influenza A and B viruses which is required for release of progeny virus. Inhibitors of NA possess anti-influenza effects, and the catalytic site structure is conserved among all known influenza viruses. NA inhibitors should provide broad spectrum anti-influenza actions which the virus cannot readily evade by mutation. The goal of this project is to use combinatorial chemistry and structure-based drug design to develop orally active NA inhibitors as broad spectrum anti-influenza drugs. Parainfluenza, is a major cause of respiratory disease in infants, yet no effective vaccines or drugs are available. Like influenza, parainfluenza requires a neuraminidase activity found in the hemagglutinin-neuraminidase (HN) protein. We will target the HN to develop orally active drugs effective against parainfluenza. We have developed chemically simple, low nM inhibitors of influenza neuraminidase, but these are currently selective for type A. We will continue to optimize these agents and begin drug development targeted to a second virus, parainfluenza. The Specific Aims are: (1) Further optimize the activity of compounds within our most active class of inhibitors for influenza A; (2) Extend the activity of these inhibitors to include influenza B; (3) Identify any mutations that arise from passage of the influenza virus in the presence of our nM inhibitors and next generation inhibitors; (4) Apply the approaches successful for influenza NA to a new target, the HN of parainfluenza virus.