Developing Inhibitors of Bacterial and Trypanosomal CTP Synthases

Trypanosomal infections present major health problems for humans and livestock in sub-Saharan Africa. In 2008, African trypanosomiasis (or sleeping sickness) killed ~48,000 people. In addition, the disease in domestic animals, particularly cattle, poses a serious impediment to the economic development of affected rural areas. Another trypanosomal infection, known as American trypanosomiasis or Chagas disease, occurs mainly in Latin American countries. It causes heart disease and digestive problems in chronic cases and is a concern for tourists. Unfortunately, treatments for these infections suffer from several problems including failure, adverse reactions, and continued availability. Consequently, there exists a need for well-tolerated and easy to use medications to treat these infections. The enzyme cytidine 5'-triphosphate (CTP) synthase (CTPS) catalyzes the production of CTP, which is utilized in cells for many functions including the manufacture of genetic material and cell membranes. The trypanosome parasite that causes African sleeping sickness (T. brucei) lacks the ability to salvage old cytidine/cytosine from broken down CTP to make new CTP and must make CTP "from scratch". Hence, the parasite CTP synthase is a target for drug development. Guanosine 5'-triphosphate (GTP) activates CTPS activity; however, our laboratory recently discovered that in some organisms elevated concentrations of GTP actually inhibit the action of CTPS. For example, human CTPS is not inhibited by GTP but the enzymes from bacteria and T. brucei are inhibited by GTP and related compounds. We will extend our discoveries through studies to identify the inhibitor binding site on CTPS and the molecular features of the inhibitor required for its binding to CTPS. Using this information, we will design and synthesize more potent CTPS inhibitors to serve as lead compounds for the development of new drugs directed against African sleeping sickness and other trypanosomal infections.