Grant: Project Grant

Parasitic protozoans are one-celled organisms that cause a host of human diseases, including malaria (e.g. Plasmodium falciparum), toxoplasmosis (Toxoplasma gondii), leishmaniasis (e.g. Leishmania donovani) and amoebic dysentery (e.g. Entamoeba histolytica) among many others. Although these diseases predominate in tropical countries, they can affect Canadians as a result of travel or contact with visitors. Some like toxoplasmosis infect ~23% of the US population and usually produce only mild symptoms, but can severely harm immunocompromised persons or a fetus exposed in the 1st 2 trimesters. In contrast, the World Health Organization estimated 198 million cases of malaria worldwide with >500,000 deaths in 2013. Recently, cladosporin, a fungal metabolite we studied, was shown to inhibit a key enzyme in some of these parasites (lysyl tRNA synthetase) that is required for their protein synthesis. Cladosporin does not inhibit the corresponding human enzyme and is promising lead for development of new pharmaceuticals. However, it is not very water soluble and requires modification to become a useful drug. Our group recently identified the genes for cladosporin production and also made some analogs by both chemical synthesis as well as by biochemical transformation. We propose to extend these studies to make water soluble cladosporin analogs and to test their activity initially against the malaria-causing Plasmodium falciparum (in collaboration with Dr. Elisabeth Winzeler at University of Calfornia San Diego). We also propose to test the target proteins from at least two other parasitic protozoans to determine if they are inhibited by our cladosporin analogs. The results will provide significant amounts of drug candidates for study and will allow their assessment as possible therapeutic agents for malaria and other protozoan diseases. It will also reveal whether the lysyl tRNA synthetase enzyme target is appropriate to prevent such diseases without harming mammals