Implications of Cruzain and its pro-peptide in Chagas disease: bottom-up approach study of the folding mechanism of Cruzain

Cruzain is the major cysteine proteinase of Trypanosoma cruzi, the parasitic protozoan causing the American Trypanosomiasis, Chagas  disease. Chagas disease is a chronic infection caused by Trypanosoma cruzi and remains prevalent in Central and South America and is gradually making its way to other countries. Though the disease causes death in only a small number of infected patients, most treatments are unsatisfactory and no vaccine is yet discovered. The reason so many cases of Chagas disease still exists is due to the life cycle, resistance to medication, and the continued transmission of Trypanosoma cruzi. The enzyme Cruzain is a virulence factor of the parasite, important in the host/parasite relationship, and is considered a very promising target for chemotherapy of the disease. We want to study the implications of Cruzain protein (a cystein protease) in the prevention of Chagas disease by introducing a bottom-up approach via studying the folding mechanism of Cruzain. Our main aim is to determine intramolecular interactions made between the pro-domain of cruzain and cruzain; the pro-domain is a known inhibitor for other enzymes including serine and alpha lytic proteases. Point mutations made on cruzain and its isolated pro-domain will help elucidate the interactions between these two domains. In our study, we would like to prevent the protein from gaining three dimensional structure and prevent its function.