Analysis of the antimalarial properties of histone deacetylase inhibitors in wild-type Plasmodium falciparum and knockdown of nuclear protein PfMORC

• Grant number: 24/09115-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): November 01, 2024
• Effective date (End): October 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal Investigator: Célia Regina da Silva Garcia
• Grantee: Pedro Negrão Maiolini
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Malaria is a disease caused by protozoan parasites of the genus Plasmodium that results in the death of hundreds of thousands of people every year. Due to the resistance that the etiological agent has acquired to available antimalarials, increasingly more research has been carried out into the biology of the parasite in order to elucidate its signaling pathways and discover targets for the development of new antimalarials.Histone deacetylases (HDACs) are important for chromatin condensation and regulating gene expression. HDAC inhibitors have been used as antitumor and antiparasitic agents, and different HDAC inhibitors have been identified as inhibitors of the intraerythrocytic cycle of Plasmodium falciparum. In this context, new antimalarials may be discovered from screening trials for HDAC inhibitors.GPCRs (G-protein coupled receptors), present in various organisms, are characterized by the presence of 7 transmembrane domains and are the targets of most of the drugs available on the market. Four serpentine receptors have been identified in the Plasmodium falciparum genome, called SR1, SR10, SR12 and SR25. The study of functional aspects of GPCR candidates can contribute to elucidating aspects of Plasmodium biology, such as the signaling pathways involved in life cycle synchronicity and drug resistance.The project will address the screening of histone deacetylase inhibitors to analyze their effects on the parasitemia of Plasmodium falciparum cultures. In addition, we will investigate by fluorescence microscopy the intracellular localization of GPCR candidates in HEK293T cells treated with HDAC inhibitors.