G-Protein Coupled Receptors as Drug Targets to Treat Schistosomiasis

Abstract

Different species of schistosomes, primarily Schistosoma haematobium, S. mansoni, and S. japonicum, are responsible for schistosomiasis, which affects over two hundred million people annually in the undeveloped world. If this disease is left untreated, it can lead to several major health complications, such as cancer, infertility, and liver fibrosis. With no available vaccine and the fear of a significant potential public health threat arising due to the parasite becoming resistant to the only known treatment, praziquantel, exploring alternative therapies is critical. The goal of my thesis project is to explore new schistosome drug targets. G-protein coupled receptors (GPCRs) are logical druggable targets given that they control key aspects of schistosome biology, such as neuromuscular functions and reproduction. There have been recent updates to the genome assemblies of each of the three major species of schistosomes. Studies on these GPCRs will require accurate and updated genome annotation. I reannotated the repertoire of GPCRs present in the three major schistosome species and identified 17 new S. mansoni GPCRs, 43 new sequences for S. haematobium, and 61 sequences for S. japonicum (to my knowledge, the first annotation of S. japonicum GPCRs). I selected several class A neuropeptide receptors from the S. mansoni genome with high gene expression, which are being prioritized for this project. These receptors represent a large segment of GPCRs and can bind one or more neuropeptides. Using gene-specific primers, 11 out of 15 genes with high expression were cloned and are presently being extended to full length using 5’ / 3’ RACE. With a complete cloned sequence of those genes, the functionality will be tested to identify possible ligands that engage the receptors and thus provide information on their pharmacology.