Novel anti-viral agents to treat influenza

DESCRIPTION provided by applicant Yearly influenza epidemics affect about of the worldandapos s population and estimates of annual mortality range from including approximately deaths and hospitalizations in the United States In addition the likelihood of a severe pandemic caused by a newly emergent strain of influenza virus is very high given that three such pandemics were recorded in the th century plus the andquot swineandquot H N pandemic of The most devastating of these the Spanish influenza was associated with an estimated million deaths worldwide The annual vaccine for seasonal influenza is only partially effective in prevention of disease Likewise currently available anti influenza drugs such as amantadine and oseltamivir are only partially effective in treatment prophylaxis and also suffer from problems of drug resistance Therefore there is an urgent need for additional anti influenza therapeutics that target unexploited aspects of viral biology The proposed studies are directed at developing new drugs that can combat influenza virus The viral NS protein is an attractive drug target because it is essential for virus replication in vivo Small molecules that inhibit NS function are expected to block virus replication and hence disease During Phase I two chemical series were developed that specifically inhibit NS function during infection These compounds inhibit virus replication in cell culture and an animal model The goal for Phase II is to develop these series to be ready for IND enabling pharmacology and toxicology in Phase III In Aim medicinal chemistry approaches will be used to create highly potent non toxic analogs In Aim purified NS protein will be used in biochemical assays to determine binding constants for the newly synthesized analogs and X ray crystallography will be employed to understand the structure of ligand drug complexes These methods will support the design of better NS inhibitors In Aim the analogs will be assessed according to several criteria including antiviral activity cytotoxicity induction of cellular interferon and in vitro ADME properties Aim will culminate with in vivo testing in BALB c mice including MTD PK and efficacy studies PUBLIC HEALTH RELEVANCE Yearly influenza epidemics affect about of the worldandapos s population and estimates of annual mortality range from including approximately deaths and hospitalizations in the United States The proposed research is directed at developing new drugs that can combat influenza virus the virus that causes influenza