Assessment of activity and mechanism of action of synthetic compounds against Toxoplasma gondii

• Grant number: 24/10179-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2024
• End date: July 31, 2025
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Juliana Quero Reimão Dalla Zanna
• Grantee: Tayline Torres
• Host Institution: Faculdade de Medicina de Jundiaí (FMJ). Prefeitura Municipal de Jundiaí. Jundiaí , SP, Brazil
• Associated research grant: 18/18954-4 - Drug repurposing: evaluation of activity, selectivity and mechanism of action of new drug candidates against Toxoplasma gondii, AP.JP

Abstract

Introduction: Toxoplasmosis, caused by the parasite Toxoplasma gondii, has a worldwide distribution and can be found in approximately 30% of the population. Despite its high prevalence, the disease has a limited therapeutic arsenal, consisting of medications with limited efficacy and considerable toxic effects. In this context, the search for new anti-T. gondii drugs becomes necessary, aiming to find safer and more effective medications against both acute and chronic forms of the disease. Objectives: The aim of this study is to identify among synthetic compounds originally developed for other diseases those with anti-T. gondii activity and investigate their mechanism of action against the parasite. Method: Screening of synthetic compounds will be performed against intracellular tachyzoites of T. gondii and human foreskin fibroblasts (HFF). Compounds will be selected based on concentrations capable of inhibiting the parasite while maintaining the integrity of host cells. The values of 50% Effective Concentration (EC50), 50% Cytotoxic Concentration (CC50), and Selectivity Index (SI) of the most promising compounds will be determined. Compounds with high SI and desirable characteristics of absorption, distribution, metabolism, excretion, and toxicity (ADMET) will be selected. At least one of these compounds will undergo phenotypic assays to investigate the mechanism of action against T. gondii and in vivo assays to evaluate efficacy in treating toxoplasmosis in infected mice. Expected Results: This study is expected to contribute to the discovery of new, safer, and more effective candidates against toxoplasmosis.