Project 463958

Chagas disease (ChD) is a global health threat affecting over 8 million people and caused by the parasite Trypanosoma cruzi (T. cruzi). ChD is found primarily in South and Central America but has spread to Europe, Japan, Australia, the United States, and Canada. Due to population migration and climate change, it also poses outbreak threats with economic and health impacts worldwide. The global financial burden of ChD amounts to 7.19 billion USD/year resulting from reduced productivity, high mortality, and increased care costs associated with cardiovascular diseases (CVDs). ChD initiates with flu-like symptoms and develops into a chronic disease often manifested by cardiac diseases including cardiomyopathy, arrhythmias, and heart failure contributing to stroke and death. The drug benznidazole is available for treating the acute stage, but it is inefficient for treating the chronic stage and is highly toxic. Hence, new drugs are urgently needed. We posit that interventions targeting the parasite can reduce CVDs, especially in ChD endemic areas. Therefore, we propose developing new drugs against T. cruzi parasites and studying drugs' mode of action. Using structure-based rational drug design, we will generate highly effective and selective candidate drugs against T. cruzi. We will evaluate the efficacy and selectivity of the new drug candidates against several parasite strains. We propose testing candidate drugs' toxicity against cardiac and non-cardiac cells and their effect on Chagas-induced CVD models. Moreover, we propose identifying the drugs' mechanisms of action by revealing the proteins targeted by candidate drugs using genomic technologies and biochemical assays. We will test the ability of candidate drugs to cure animals infected with T. cruzi and reduce the cardiovascular burden. Hence, this project will generate new drug candidates for treating ChD and reducing associated cardiovascular diseases.