The long-term objective for this project is to develop inhibitors of glycoprotein processing as anti-viral agents for the clinical treatment of influenza virus infection. We postulate that post-translational modification of viral glycoproteins, relating to the processing of Nlinked oligosaccharides by a-glucosidase 1, will alter their function and inhibit the virus life cycle. Evidence exists that the various functions of haemagglutinin (HA)/neuraminadase (NA) are reliant on correct glycosylation. Our lead molecules are established ct-glucosidase 1 inhibitors. The research plan for Phase I entails dose-response studies in vitro against representative influenza virus A and B strains to establish 50 percent inhibitory concentrations (IC5o). Combination studies with known inhibitors with alternative mechanisms of action will also be performed. IC5o values in the submicromolar range for compound alone or in combination will be considered a positive proof-of-concept. Molecules meeting this criteria will be advanced to a rodent model of influenza virus infection. Even with the recent introduction of NA inhibitors as therapeutics, influenza virus infection remains a increasing problem in transplant recipientsand other immuno-suppressed patients. We anticipate a further need for influenza virus inhibitors with a novel mechanism of action to be used in combination with existing modalities. PROPOSED COMMERCIAL APPLICATION: Virogen USA, will develop novel alpha-glucosidase 1 inhibitors as anti-influenza agents to be used alone and in combination with existing therapeutics. Influenza virus infections represent a growing problem to which the pharmaceutical industry continues to seek improved therapeutic solutions.
