In silico screening and in vitro investigation of the mechanism of action of candidates for cerebral toxoplasmosis therapy

• Grant number: 23/18327-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2024
• End date: June 30, 2026
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Juliana Quero Reimão Dalla Zanna
• Grantee: Gabriel Cândido Moura
• 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

Toxoplasmosis, caused by the protozoan Toxoplasma gondii, poses a global threat, affecting approximately one-third of the world's population. While often asymptomatic, the infection can be fatal, particularly in immunocompromised individuals, leading to toxoplasmic encephalitis. The current treatment, based on pyrimethamine and sulfadiazine, exhibits limited efficacy and issues related to toxicity and parasitic resistance. In light of this scenario, this project aims to identify new therapeutic candidates through drug repositioning. In this regard, Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) prediction tools will be employed to select compounds with predicted capability to cross the blood-brain barrier and low toxicity. In vitro tests against T. gondii tachyzoites and human fibroblasts will be conducted to assess the compounds' selectivity. Additionally, genetic investigation of potential targets in the most promising compounds will be performed. The complexity of the current treatment and the increasing parasitic resistance underscore the urgent need for more effective and specific therapeutic alternatives. The proposed approach, combining the identification of compounds from repositioning libraries with anti-T. gondii activity and potential brain permeation, offers an innovative strategy for discovering new therapeutic candidates. It is anticipated that the identification of more selective candidates with the potential to reach therapeutic levels in the brain will contribute to cerebral toxoplasmosis treatment. This pathway aims not only for enhanced efficacy but also compliance with current clinical safety standards.