The goal of this R21 Exploratory/Developmental Research proposal is to identify the function of the only cytochrome P450 protein present in Schistosoma mansoni, a causative agent of schistosomiasis. We hypothesize that the unique schistosome cytochrome P450 is essential for worm communication, survival, reproduction, and development and that its function can be identified by linking it to specific metabolic pathways. We believe that understanding the function of this protein will identify critical signaling pathway and will be useful in the discovery of new drugs for schistosomiasis, an important, neglected disease with more than 200 million people infected resulting in 200,000 deaths annually and untold chronic illness and disability. Only one drug is available for schistosomiasis treatment and there are concerns that drug resistance is evolving.
The goal of this R21 Exploratory/Developmental Research proposal is to identify the function(s) of the only cytochrome P450 protein present in Schistosoma mansoni. We believe that understanding the function of this protein will identify critical signaling pathways and will be useful in the discovery of new drugs for schistosomiasis. We hypothesize that schistosome cytochrome P450 is essential for worm communication, survival, reproduction, and development and that its function can be identified by linking it to specific metabolic pathways. In humans there are ~100 cytochrome P450 proteins, which have numerous important functions in reproduction, development, and defense against infections and toxic compounds. The function of S. mansoni cytochrome P450 protein is unknown; it is an 'orphan' cytochrome P450. Our preliminary results indicate that S. mansoni cytochrome P450 mRNA is present in all developmental stages, but at 100s-fold different abundances. We have also found that S. mansoni cytochrome P450 is an essential protein and targeted by clinically used antifungal compounds. We propose to 'deorphanize'S. mansoni cytochrome P450 through identification of metabolites that are its substrates and products, which will link CYP450 to specific metabolic pathways. We will use cutting edge metabolomic platforms for quantitative, untargeted and targeted metabolite profiling of worm metabolites. We will also explore the pharmacology of antifungal azole as worm cytochrome P450 inhibitors and leads for drug development. Schistosomiasis is an important, neglected disease with more than 200 million people infected resulting in 200,000 deaths annually and untold chronic illness and disability. Only one drug is available for schistosomiasis treatment and there are concerns that drug resistance is evolving. These studies will lead to the identification of new pathways, enzymes, and drug targets and will be the foundation for further functional and structural investigations on this enzyme.
