Interaction of drugs as potential inhibitors of the isoprenoid pathway in Plasmodium falciparum and Plasmodium berghei

• Grant number: 18/09106-0
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): December 01, 2018
• Effective date (End): January 31, 2021
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Alejandro Miguel Katzin
• Grantee: Norma Lucía Buriticá Zuluaga
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Malaria remains one of the major public health problems affecting about half the world's population. According to WHO, in 2016, 216 million cases of malaria and 445 thousand deaths were registered. This disease caused by parasites of the genus Plasmodium is difficult to eradicate, so it is necessary to seek new targets for the development of more effective chemotherapeutic agents to control the infection.Our laboratory in recent years has been focusing on the study of possible inhibitors of the isoprenoid pathway in P. falciparum, which are synthesized via the 2C-methyl-D-erythritol-4-phosphate (MEP) pathway. This pathway being active in the intra-erythrocytic stage of the parasite and not shared with the human host, becomes an interesting target for the development of new antimalarials.Isoprenoids are a diverse group of natural products with many functions and their synthesis is essential for the survival of the parasite. In recent years, many drugs have been tested as blockers of isoprenoid synthesis in Plasmodium, and have allowed us to identify the different targets of action of these drugs as potential antimalarial drugs. In addition, as already demonstrated by us, combinations of drugs that act on different targets of the isoprenoid pathway in the parasite have important supra-additivity effects.Taking into account the above, in this study we will use two methodologies known to evaluate the synergism of 9 antimalarial drugs tested previously, and individually reduce the growth of Plasmodium falciparum "in vitro" through the inhibition of isoprenoid biosynthesis, and finally evaluate " in vivo "through Plasmodium berghei ANKA infection combinations of drugs that show additive or potentiating synergistic effects.