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

• Grant number: 14/23417-7
• Support Opportunities: Regular Research Grants
• Duration: July 01, 2015 - February 28, 2018
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Alejandro Miguel Katzin
• Grantee: Alejandro Miguel Katzin
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Emilia Akemi Shiraishi Kimura ; José Mário de Freitas Balanco

Abstract

A fact which leads to an increase in morbidity and mortality of malaria in the world is the resistance to chemotherapeutic agents that the parasite presents. Therefore, it is necessary to identify new potential targets specific in the parasite for to implement a rational planning. The present project proposes complement the studies that are being developed in our laboratory on the biosynthesis of isoprenoids in intraerythrocytic stages of Plasmodium falciparum. All of the isoprenoids derive from a common precursor, isopentenyl diphosphate and its isomer dimethylallyl diphosphate, being the enzymes prenyltransferases responsible for catalyzing the condensation sequence of isoprenic units. An active pathway biosynthesize phylloquinone, menaquinone and tocopherol in intraerythrocytic stages of P. falciparum were recently demonstrated in our laboratory. In this project we propose to evaluate the antioxidant activity of ±-tocopherol, ³-tocopherol and phylloquinone in intraerythrocytic Plasmodium falciparum stages, as well as to characterize the presence of free from the degradation of phytol and tocopherol phylloquinone and check if these vitamins may be biosynthesized from phytol. In a bifunctional enzyme octaprenil-PP synthase/phytoene synthase kinetic studies and their interaction with nerolidol and squalestatin and verifying the specificity of these inhibitors by over-expression of this enzyme in the parasite inhibitors will be finalized. The isoprenoid farnesyl-PP specifically binds to the heme ring in order to be located in the mitochondria of the cells. Heme biosynthesis in malaria parasites is a hybrid shared and unique path between the mitochondria and apicoplast therefore intend to identify the heme and heme A as well as COX10 COX15 and enzymes during the intra-erythrocytic development in Plasmodium falciparum. With the results obtained in vitro in the previous project we will evaluate in this project squalestatin and nerolidol as potential antimalarial drugs in vivo in Plasmodium berghei-infected mice. (AU)

Scientific publications

(7)

(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)

SAITO, ALEXANDRE Y.; MARIN RODRIGUEZ, ADRIANA A.; MENCHACA VEGA, DANIELLE S.; SUSSMANN, RODRIGO A. C.; KIMURA, EMILIA A.; KATZIN, ALEJANDRO M.. Antimalarial activity of the terpene nerolidol. INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS, v. 48, n. 6, p. 641-646, DEC 2016. (14/23417-7)

SAITO, ALEXANDRE YUKIO; SUSSMANN, RODRIGO ANTONIO CESCHINI; KIMURA, EMILIA AKEMI; CASSERA, MARIA BELEN; KATZIN, ALEJANDRO MIGUEL. Quantification of nerolidol in mouse plasma using gas chromatography-mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis, v. 111, p. 100-103, JUL 10 2015. (14/23417-7)

SUSSMANN, RODRIGO A. C.; DE MORAES, MARCILIO M.; CEBRIAN-TORREJON, GERARDO; PORTA, EXEQUIEL O.; DOMENECH-CARBO, ANTONIO; YAMAGUCHI, LYDIA F.; KATZIN, ALEJANDRO M.; KATO, MASSUO J.. Stabilization and detection of hydrophylloquinone as di-O-methyl derivative. JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES, v. 1033, p. 368-371, OCT 15 2016. (14/23417-7)

DE SENA PEREIRA, VALESKA S.; EMERY, FLAVIO DA SILVA; LOBO, LIS; NOGUEIRA, FATIMA; OLIVEIRA, JONAS I. N.; FULCO, UMBERTO L.; ALBUQUERQUE, EUDENILSON L.; KATZIN, ALEJANDRO M.; DE ANDRADE-NETO, VALTER F.. In vitro antiplasmodial activity, pharmacokinetic profiles and interference in isoprenoid pathway of 2-aniline-3-hydroxy-1.4-naphthoquinone derivatives. Malaria Journal, v. 17, DEC 19 2018. (14/23417-7)

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. (17/22452-1, 14/23417-7, 15/12054-3, 15/19316-3, 16/15298-3)

MASSAD, TARA J.; DE MORASS, MARCILIO MARTINS; PHILBIN, CASEY; OLIVEIRA, JR., CELSO; TORREJON, GERARDO CEBRIAN; YAMAGUCHI, LYDIA FUMIKO; JEFFREY, CHRISTOPHER S.; DYER, LEE A.; RICHARDS, LORA A.; KATO, MASSUO J.. Similarity in volatile communities leads to increased herbivory and greater tropical forest diversity. ECOLOGY, v. 98, n. 7, p. 1750-1756, JUL 2017. (14/23417-7)

GABRIEL, HELOISA B.; DE AZEVEDO, MAURO F.; PALMISANO, GIUSEPPE; WUNDERLICH, GERHARD; KIMURA, EMILIA A.; KATZIN, ALEJANDRO M.; ALVES, JOAO M. P.. Single-target high-throughput transcription analyses reveal high levels of alternative splicing present in the FPPS/GGPPS from Plasmodium falciparum. SCIENTIFIC REPORTS, v. 5, DEC 21 2015. (13/14622-3, 10/19518-1, 14/23417-7)