Functional characterization of compounds that interfere with intracellular development of Trypanosoma cruzi

• Grant number: 15/06489-7
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: November 01, 2015
• End date: July 31, 2018
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Lucio Holanda Gondim de Freitas Junior
• Grantee: Adalberto Miguel de Araújo Júnior
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Since American trypanosomiasis was discovered, numerous studies have been done to know more about the pathogenesis of the Chagas Disease. Even though there has been progress in researches regarding such malady, Trypanosoma cruzi biology remains still poorly understood in comparison to other trypanosomatids and proteins involved in the differentiation remain poorly characterized, and less is known about the environmental and host factors that may trigger this process. Cell-based phenotypic screenings have been successfully used for target discovery and validation in some protozoan parasites when gene knockdown tools such as RNAi are not available and for T. cruzi offer an interesting approach to investigate its biology. The present project intends to develop a high content screening assay to enable the discovery of compounds capable of modulating T. cruzi intracellular infection, thus generating chemical probes that will aid the discovery of molecular players behind the differentiation processes in Trypanosoma cruzi and possibly generate new drug candidates for antichagasic chemotherapy. In preliminary assays, we focused our researches in kinases as potencial target for T. cruzi due to their participation in parasite morphology, proliferation, differentiation and overall viability. A high-content screening against T. cruzi using a targeted library of 4000 anti-kinase/phosphatase compounds was perform and compounds capable of interfering with the parasite intracellular development were identified. Therefore, we will attempt to validate these phenotypic hits, optimize the high-content screening protocol, elucidate by different techniques the target involved with the phenotypic hits and perform a second primary screening in order to identify effective compounds against the chronic stage of Chagas Disease. (AU)