About This Project

The etiological agent for Chagas' disease is the protozoan parasite Trypanosoma cruzi, which affects 6 - 7 million people primarily in Latin America. The chronic stage of infection causes cardiomyopathy and the enlargement of other organs resulting in disease burden and death. There is an urgent need to replace the clinical therapeutics (benznidazole & nifurtimox) and this proposal focuses on a compound screen to observe a hit expansion with the target T. cruzi glucokinase.

Ask the Scientists

What is the context of this research?

Chagas' disease (CD) is a neglected tropical disease (NTD) that causes cardiomyopathy and the enlargement of other organs ultimately resulting in disease burden and death. The etiological agent for CD is Trypanosoma cruzi, which is a unicellular parasite that infects its host cells. Critically important to the parasite's survival is the metabolite glucose-6-phosphate (G6P). An enzyme that produces G6P is T. cruzi glucokinase (TcGlcK) and its inhibition has been shown in various medicinal chemistry studies to result in cell death. The underlying goal of this research is to replace the clinically available therapeutics such as benznidazole and nifurtimox as they are responsible in unwanted side effects. We have an interest in discovering novelTcGlcK inhibitors.

What is the significance of this project?

Our proposed research aims at identifying viable drug leads by illuminating on a promising core scaffold identified from a high-throughput screen of 13,040 compounds that was published in 2019. We plan to perform a hit expansion by running a primary screen from a custom chemical library of <100 compounds. The hits will be compared to our HTS campaign. It is expected that the primary screen against TcGlcK will reveal more potent analogues. This contribution is significant because it is expected to lead to a new therapeutic candidate that will surpass the effectiveness of benznidazole and/or nifurtimox.

What are the goals of the project?

The main goal for the project is to observe a hit-expansion by running a focused screen. The compound library we plan to purchase will include less than 100 compounds that are very similar in structure to the original confirmed hit identified forTcGlcK from the HTS campaign. Once we learn which compounds inhibit TcGlcK, we will perform in vitro biological assays at a future date, which is beyond the scope of this proposal.