Evaluation of the effect of metallodrugs on Trypanosoma cruzi

• Grant number: 25/01266-1
• Support Opportunities: Scholarships in Brazil - Master
• Start date: July 01, 2025
• End date: March 31, 2027
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Fernanda Ramos Gadelha
• Grantee: Vitor Klipel da Silva Bertolini
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Trypanosoma cruzi is the etiological agent of Chagas disease (CD). Currently, treatment is limited to a single drug that is not effective in the chronic phase and leads to serious side effects, making the search for a new drug a priority. The group of Prof. Camilla Abbehausen, from IQ-UNICAMP, has been studying, together with Prof. Danilo Miguel, from IB-UNICAMP, the effect of metallodrugs of phosphine and carbene classes on Leishmania sp. (FAPESP: 2022/02618-0). One of the targets of these compounds is trypanothione reductase, which plays a key role in the parasite's defense against reactive oxygen and nitrogen species. In this project, we will expand this study to other trypanosomatids, in this case T. cruzi, since preliminary tests with gold complexes of the phosphine class have shown promise. The aim of this project is to evaluate the effect of 6 metallodrugs from two different classes (carbenes and phosphines), 3 from each class, which will be developed by Prof. Camilla's group, on 3 T. cruzi isolates from patients with CD and a reference strain (Y). We will determine the EC50, CC50 for fibroblasts and the selectivity index (SI) of these compounds. We will select the most promising ones (low EC50 and excellent SI) and analyze their effects on mitochondrial bioenergetics, production of reactive oxygen species and trypanothione reductase activity. In parallel, we will analyze the effects of these compounds in in vitro infections, as well as in combination with benznidazole. The development of this project, through the deepening of the understanding of the mechanisms of action of metallodrugs, may contribute to the development of promising therapeutic options for the treatment of CD. (AU)