Grant: Operating Grant - Priority Announcement: Infection and Immunity (Bridge Funding)

The influenza virus infects ~10% of the human population each year, resulting in hundreds of thousands of deaths. Even within North America, nearly 40,000 annual "excess deaths" are attributed to influenza or to secondary bacterial infections. Despite a World Health Organization-monitored vaccine program, the disease remains a significant global health issue, requiring the use of antiviral drugs like oseltamivir (Tamiflu). A significant problem in controlling the spread of influenza is the emergence of strains that are resistant to oseltamivir. Resistance has increased tremendously in recent years (from ~1% to 98% in certain strains of influenza), pointing toward the need for second-generation drugs. The Wulff and Boulanger groups have developed a new class of antiviral agents that function by a similar mechanism to oseltamivir, but which should be more resistant to evolved mutation. These compounds are also much easier to synthesize than oseltamivir, which should permit more extensive structural optimization. We are applying for funding to (1) further improve the design of our molecules, resulting in improved activity; (2) study the binding of our most potent compounds by structural and kinetic means; (3) conduct a series of cell-based influenza inhibition assays. If these early experiments (which will require 3 years) are successful, we plan to pursue additional support for a more extensive series of trials in animals.