Grant: Proof of Principle Program - Phase I

Influenza is a severe infection of the upper respiratory tract that occurs globally each year, developing in approximately 20% of the world's population. Annually, more than 3.5 million people die of influenza and over 1.3 billion are afflicted. In the US alone approximately 314,000 hospitalizations per year are caused by non-pandemic influenza, with 30-40,000 deaths. Canada has approximately 10,000 deaths per year due to seasonal influenza. Direct costs of medical care and hospitalizations are estimated at billions worldwide. The emergence of human cases of avian influenza (H5N1) and the swine flu (H1N1) pandemic has dramatically increased concern. The currently available drugs for treatment, Tamiflu and Relenza, work by shutting off the ability of the influenza virus to escape from infected lung cells by inhibiting a key viral enzyme known as a neuraminidase. When used to treat influenza these drugs shorten the length of the infection and decrease its severity. When used prior to infection they are effective as prophylactics and play an important role in pandemic planning. Unfortunately influenza virus strains have emerged that are resistant to Tamiflu, creating an urgent need for new drugs of different structure. The fluorosialics are a new class of neuraminidase inhibitor developed by the Withers laboratory. Since the compounds are extremely similar in structure to the natural sialic acid and function as inhibitors via the same mechanism as that involved in substrate cleavage, they should be much less prone to the development of viral resistance. Initial in vitro cell-based studies have shown that these compounds can act as potent antiviral agents. The studies proposed here are aimed at evaluating the efficacy of these compounds as antiviral agents in vivo as well as determining optimal structures and dosages and further assessing potential toxicity. If effective they may represent a whole new class of agent.