The Sphingolipid Biosynthetic Pathway Is a Potential Target for Chemotherapy against Chagas Disease

Abstract

The protozoan parasiteTrypanosoma cruziis the causative agent of human Chagas disease, for which there currently is no cure. The life cycle ofT. cruziis complex, including an extracellular phase in the triatomine insect vector and an obligatory intracellular stage inside the vertebrate host. These phases depend on a variety of surface glycosylphosphatidylinositol-(GPI-) anchored glycoconjugates that are synthesized by the parasite. Therefore, the surface expression of GPI-anchored components and the biosynthetic pathways of GPI anchors are attractive targets for new therapies for Chagas disease. We identified new drug targets for chemotherapy by taking the available genome sequence information and searching for differences in the sphingolipid biosynthetic pathways (SBPs) of mammals andT. cruzi. In this paper, we discuss the major steps of the SBP in mammals, yeast andT. cruzi, focusing on the IPC synthase and ceramide remodeling ofT. cruzias potential therapeutic targets for Chagas disease.