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Biosynthesis of isoprenoids in Plasmodium falciparum: evaluation of possible targets to obtain new anti-malarial drugs

Grant number: 17/22452-1
Support type:Research Projects - Thematic Grants
Duration: April 01, 2018 - March 31, 2023
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal researcher:Alejandro Miguel Katzin
Grantee:Alejandro Miguel Katzin
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers: Alicia Susana Couto ; Emilia Akemi Shiraishi Kimura ; Fernando Gonçalves de Almeida ; Guillermo Labadie ; Leonardo José de Moura Carvalho ; María Belén Cassera ; Massuo Jorge Kato ; Mauro Ferreira de Azevedo
Associated scholarship(s):21/09516-6 - Biosynthesis of isoprenoids in Plasmodium falciparum. Evaluation of possible targets to obtain new anti-malarial drugs., BP.TT
21/01877-0 - Study the inhibition ubiquinone biosynthesis in Leishmania (L.) amazonensis as a strategy in the discovery of new therapeutic targets, BP.PD
20/12563-3 - Evaluation of the biochemical characteristics of P. falciparum resistant to atovaquone, BP.IC
+ associated scholarships 20/11381-9 - Biosynthesis of isoprenoids in Plasmodium falciparum. Evaluation of possible targets to obtain new anti-malarial drugs, BP.TT
19/13832-0 - Biosynthesis of isoprenoids in Plasmodium falciparum. Evaluation of possible targets to obtain new anti-malarial drugs., BP.TT
19/08634-5 - Study of prenylquinones aromatic origin in Plasmodium falciparum, BP.DD
18/02924-9 - Isoprenoid precursor transport as fosmidomycin recrudescence factor in intraeritrocytic stages of Plasmodium falciparum, BP.PD - associated scholarships


A fact which favors the increase in morbidity and mortality from Malaria in the world is the resistance to chemotherapeutic agents that the parasite presents. Therefore, it is necessary to identify new potential targets specific to the parasite, in order to be able to perform a rational planning. This project intends to complement the studies that are already being developed in our laboratory for over 20 years on the biosynthesis of isoprenoid in the intraerythrocytic stages of Plasmodium falciparum. All isoprenoid derive from a common precursor, isopentenyl diphosphate and its isomer, dimethylallyl diphosphate and the prenyltransferases are the enzymes responsible for catalyzing the condensation sequential of isoprenic units. Several intermediaries and final products of this pathway were identified in the parasite and lead us to the conclusion that it is different from the vertebrate host. Therefore, we can identify potential targets for evaluating antimalarial drugs. In these contexts we propose to study the function of an enzyme bi-functional which is key in biosynthesis of isoprenoid the farnesyl-PP/geranylgeranyl-PP synthase, in addition to investigate itself there is a futalosine pathway, described only in bacteria, as an intermediary in the biosynthesis of menaquinone. In the study of different routes present in parasite we propose to study biosynthesis of plastoquinone and phylloquinone (described in plants), since we already described a pathway active for the biosynthesis of carotenes, menaquinone and tocopherol as well as characterization the presence of phytol free from degradation of tocopherol and phylloquinone and check if these vitamins can be biosynthesized from phytol. These all isoprenoid's pathway identified it could be assessed as potential targets in intraerythrocytic stages of P. falciparum. With the results obtained in vitro in previous projects the objective to study the mechanisms involved in the protection afforded by the perillyl alcohol in the development of Cerebral Malaria Experimental will be done. (AU)

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Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MARIN, ADRIANA A.; MURILLO, OSCAR; SUSSMANN, RODRIGO A.; ORTOLAN, LUANA S.; BATTAGELLO, DANIELLA S.; QUIRINO, THATYANE DE CASTRO; BITTENCOURT, JACKSON C.; EPIPHANIO, SABRINA; KATZIN, ALEJANDRO M.; CARVALHO, LEONARDO J. M. Perillyl Alcohol Reduces Parasite Sequestration and Cerebrovascular Dysfunction during Experimental Cerebral Malaria. Antimicrobial Agents and Chemotherapy, v. 65, n. 5 MAY 2021. Web of Science Citations: 0.
VERDAGUER, I. B.; CRISPIM, M.; ZAFRA, C. A.; SUSSMANN, R. A. C.; BURITICA, N. L.; MELO, H. R.; AZEVEDO, M. F.; ALMEIDA, F. G.; KIMURA, E. A.; KATZIN, A. M. Exploring Ubiquinone Biosynthesis Inhibition as a Strategy for Improving Atovaquone Efficacy in Malaria. Antimicrobial Agents and Chemotherapy, v. 65, n. 4 APR 2021. Web of Science Citations: 0.
VERDAGUER, IGNASI B.; ZAFRA, CAMILA A.; CRISPIM, MARCELL; SUSSMANN, RODRIGO A. C.; KIMURA, EMILIA A.; KATZIN, ALEJANDRO M. Prenylquinones in Human Parasitic Protozoa: Biosynthesis, Physiological Functions, and Potential as Chemotherapeutic Targets. Molecules, v. 24, n. 20 OCT 2019. Web of Science Citations: 0.
PORTA, EXEQUIEL O. J.; VERDAGUER, IGNASI BOFILL; PEREZ, CONSUELO; BANCHIO, CLAUDIA; FERREIRA DE AZEVEDO, MAURO; KATZIN, ALEJANDRO M.; LABADIE, GUILLERMO R. Repositioning Salirasib as a new antimalarial agent. MedChemComm, v. 10, n. 9, p. 1599-1605, SEP 1 2019. Web of Science Citations: 0.
BALANCO, JOSE MARIO F.; SUSSMANN, RODRIGO A. C.; VERDAGUER, IGNASI B.; GABRIEL, HELOISA B.; KIMURA, EMILIA A.; KATZIN, ALEJANDRO M. Tocopherol biosynthesis in Leishmania (L.) amazonensis promastigotes. FEBS OPEN BIO, v. 9, n. 4, p. 743-754, APR 2019. Web of Science Citations: 1.
GABRIEL, HELOISA B.; AZEVEDO, MAURO F.; KIMURA, EMILIA A.; KATZIN, ALEJANDRO M. Plasmodium falciparum parasites overexpressing farnesyl diphosphate synthase/geranylgeranyl diphosphate synthase are more resistant to risedronate. Memórias do Instituto Oswaldo Cruz, v. 113, n. 10 2018. Web of Science Citations: 2.

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