New marine natural product tools for drug discovery and chemical genetics

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More than half of currently used drugs are derived from 'natural products'. Marine animals and microbes represent the greatest unexplored source of new 'natural products' for drug discovery. Our proposed research is designed to discover 'marine natural products' that will provide lead compounds for developing drug candidates for new approaches to treating: a) diabetes and obesity, b) SARS, c) rejection of organ transplants, and d) cystic fibrosis.  Diabetes affects 2 million Canadians and  costs the country 9 billion dollars annually. Patients suffering from diabetes or obesity experience shortened life expectancy and are susceptible to hypertension, cardiovascular disease, cancer, stroke, kidney failure, and blindness. Human pancreatic alpha amylase (HPA) is a promising target for the development of new drugs for treating diabetes and obesity. We are proposing to search for new inhibitors of  HPA. SARS first appeared in China and eventually spread worldwide, including to Canada. During the 2002 outbreak, 9000 individuals contracted SARS and there were 774 fatalities. There are no small molecule drugs to treat SARS. We are proposing to search for inhibitors of the SARS protease, 3CLpro, which has been identified as a promising target for developing anti-SARS drugs. Calcineurin, a protein phosphatase, is the indirect cellular target of the immunosuppressive drugs cyclosporine and FK506. Even though these are important drugs that have revolutionized organ transplantation, they have serious side effects. Despite the clinical importance of calcineurin inhibitors, there are no good active-site inhibitors of this phosphatase known. We are proposing to search for active-site inhibitors of calcineurin that would act as leads for development of a new class of immunosuppressive drugs. Cystic Fibrosis (CF) is the most common lethal genetic disease affecting Caucasians.  CF patients have an expected life span of only 34 years. CF is caused by a phenylalanine deletion (deltaF508) mutation in the CFTR gene leading to misfolding and decreased function of the CFTR gene product. We propose to search for deltaF508-CFTR defect 'correctors', which are hypothesized to be useful drugs for treating CF.