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| Author(s): |
Norma Lucía Buritica Zuluaga
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) |
| Defense date: | 2021-06-28 |
| Examining board members: |
Alejandro Miguel Katzin;
Marcos Leoni Gazarini Dutra;
Marcelo Urbano Ferreira;
Antonio Carlos Oliveira
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| Advisor: | Alejandro Miguel Katzin |
| Abstract | |
The emergence of plasmodium spp resistance to antimalarial chemotherapy currently used in therapy, make necessary to development of new drugs, or in this case, new drugs combination that to be able to inhibit different timepoints of the same metabolic pathway and thus, potentiate the antimalarial effect of these drugs and decrease the frequency of its resistance. The main racional of study in our laboratory is the inhibition of the 2C-methyl-D-erythritl-4-phosphate pathway (via MEP) in P. falciparum, responsible for the biosynthesis of isoprenoids, which is observed in the intraerythrocytic stage of the parasite and it is not share with the human host, become a potential target for drug development. In this sense, several drugs have been reported as inhibitors of this isoprenoid metabolism thorugh in vitro tests, Also, some combinations of these drugs were done and showed several effects of supra aditivity. Thus, the rationale of the current project was to evaluate 6 compounds which presents antimalarial activity by inhibition of isoprenoid pathway. These compounds were initially tested in couple combinations using 3 methodologies described by other authors which are able to identify drug interactions; and additionally, 2 drugs that are traditionally used in clinical (chloroquine and atovaquone) and 1 drug used in preclinical trials (DSM-265) were included, whose action could be improved in combination with the first 6 compounds. In addition, this project aims to compare 3 different techniques used in the study of synergisms in order to discover what is the most effective methodology for this type of study. The 9 compounds combined in pairs resulted in a total of 36 combinations, of which 4 were identified as synergistic (nerolidol-atovaquone, nerolidol-DSM265, nerolidol-risedronate and usnic acid-atovaquone), through 2 different methodologies for synergy study. Other combinations such as fosmidomycin -risedronate and fosmidomycin chloroquine showed additive interaction only when using methodology 1 (with methodology 2 there was no additive interaction between these combinations). Interestingly, many of the combinations of drugs tested can achieve the reduction of the growth of the parasite, by inhibiting the synthesis and function of many metabolic products essential for the survival of the same. Thus, this study allows us to suggest that this is an effective alternative in the search for new drug candidates to be used in combination with traditional antimalarials. (AU) | |
| FAPESP's process: | 18/09106-0 - Interaction of drugs as potential inhibitors of the isoprenoid pathway in Plasmodium falciparum and Plasmodium berghei |
| Grantee: | Norma Lucía Buriticá Zuluaga |
| Support Opportunities: | Scholarships in Brazil - Master |