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Development of new tools for search and validation of molecular targets for therapy against Plasmodium vivax

Grant number: 17/18611-7
Support type:Research Projects - Thematic Grants
Duration: September 01, 2018 - August 31, 2023
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal Investigator:Fabio Trindade Maranhão Costa
Grantee:Fabio Trindade Maranhão Costa
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Assoc. researchers:Aline Mara dos Santos ; Carolina Horta Andrade ; Daniel Youssef Bargieri ; Elizabeth Bilsland ; Leonardo José de Moura Carvalho ; Letusa Albrecht ; Marcus Vinícius Guimarães de Lacerda ; Pedro Vitor Lemos Cravo ; Per Sunnerhagen ; Robson de Queiroz Monteiro ; Rodolpho de Campos Braga ; Rogerio Amino ; Stefanie Costa Pinto Lopes ; Wuelton Marcelo Monteiro
Associated grant(s):20/05369-6 - Artificial inteligence driven drug repositioning strategy for COVID-19, AP.R
Associated scholarship(s):20/01890-3 - Cellular effects of chaperone inhibition by violacein, BP.IC
20/11060-8 - Evaluation of the impacts of activation and endothelial dysfunction induced by Plasmodium vivax in patients of the Brazilian Amazon, BP.DD
20/02158-4 - Identifying hypnozonticidal agents using chemogenomic, bioinfomatics and phenotypic strategies: focus in Plasmodium vivax, BP.PD
+ associated scholarships 19/21854-4 - Kinase prioritization and discovery of compounds with anti-malarial activity against different stages of Plasmodium vivax using chemogenomics, bioinformatics, cheminformatics, and experimental evaluation tools, BP.PD
19/02171-3 - Investigation of antimalarial activity and molecular targets of natural compounds identified by chemoinformatics against Plasmodium vivax, BP.DR
19/12693-7 - Evaluation of the effects of activation and endothelial dysfunction induced by P. vivax in patients from Brazilian endemic regions, BP.DD - associated scholarships

Abstract

Malaria caused by Plasmodium vivax is the most widely distributed Malaria form in the world. Worldwide, 2.5 billion people are at risk of Plasmodium vivax infection, with 8.5 million cases worldwide in 2015. Brazil, together with Venezuela, is the leader in cases in the Americas, 99.5% of which are reported in the region called Legal Amazon. Currently more than 85% of cases in Brazil are caused by P. vivax. P. vivax has several unique biological characteristics, such as: exclusive preference for reticulocyte infection, the production of sexual stages (gametocytes) observed in peripheral blood quite early after infection and formation of hypnozoites (a latent stage that remains in the liver). Therefore, the same control measures used for P. falciparum have revealed failures in controlling Vivax Malaria. Presently, P. vivax has been considered a pathogen that causes severe immunopathological symptoms and an increase in the resistance to chloroquine has alarmed the scientific community. Moreover, the impossibility of in vitro cultivation for long periods, along with its particular characteristics, has been challenging the understanding of the biology of this pathogen. In this proposal we intend to identify and characterize potential molecular targets of P. vivax for use in vaccine strategies and for antimalarial treatment. Also, we wish to verify the participation of molecules involved in endothelial disorders and evaluate potential inhibitors. More specifically, and considering the development of antimalarials, we intend through in silico analysis to identify kinases (mainly) as molecular targets of P. vivax and establish a technological platform for the discovery of new drugs taking into account all stages of the parasite, including hypnozoites, in which we aim to work with the recently established National Hypnozoite Research Center (FIOCRUZ-RJ), that provides models of non-human primates and infection with P. cynomolgi that will be used to evaluate both drugs and experimental vaccines generated in the previous steps. Also, by means of new-generation sequencing of the entire P. vivax transcriptome (RNA-seq) and integrated data analysis, we hope to track new targets that have not yet been considered in pre-existing databases. Finally, we intend to evaluate plasma factors of infected patients capable of interfering in endothelial functions, as well as to test specific inhibitors in a model of murine infection capable of inducing immunopathological complications. (AU)

Scientific publications (8)
(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)
HUNG, JANE; GOODMAN, ALLEN; RAVEL, DEEPALI; LOPES, STEFANIE C. P.; RANGEL, GABRIEL W.; NERY, ODAILTON A.; MALLERET, BENOIT; NOSTEN, FRANCOIS; LACERDA, MARCUS V. G.; FERREIRA, MARCELO U.; RENIA, LAURENT; DURAISINGH, MANOJ T.; COSTA, FABIO T. M.; MARTI, MATTHIAS; CARPENTER, ANNE E. Keras R-CNN: library for cell detection in biological images using deep neural networks. BMC Bioinformatics, v. 21, n. 1 JUL 11 2020. Web of Science Citations: 0.
DOS-SANTOS, JOAO CONRADO KHOURI; SILVA-FILHO, JOAO LUIZ; JUDICE, CARLA C.; KAYANO, ANA CAROLINA ANDRADE VITOR; ALIBERTI, JULIO; KHOURI, RICARDO; DE LIMA, DIOGENES S.; NAKAYA, HELDER; LACERDA, MARCUS VINICIUS GUIMARAES; DE PAULA, ERICH VINICIUS; LOPES, STEFANIE COSTA PINTO; COSTA, FABIO TRINDADE MARANHAO. Platelet disturbances correlate with endothelial cell activation in uncomplicatedPlasmodium vivaxmalaria. PLoS Neglected Tropical Diseases, v. 14, n. 7 JUL 2020. Web of Science Citations: 0.
SILVA-FILHO, JOAO LUIZ; LACERDA, MARCUS V. G.; RECKER, MARIO; WASSMER, SAMUEL C.; MARTI, MATTHIAS; COSTA, FABIO T. M. Plasmodium vivax in Hematopoietic Niches: Hidden and Dangerous. Trends in Parasitology, v. 36, n. 5, p. 447-458, MAY 2020. Web of Science Citations: 2.
NEVES, BRUNO J.; BRAGA, RODOLPHO C.; ALVES, VINICIUS M.; LIMA, MARILIA N. N.; CASSIANO, GUSTAVO C.; MURATOV, EUGENE N.; COSTA, FABIO T. M.; ANDRADE, CAROLINA HORTA. Deep Learning-driven research for drug discovery: Tackling Malaria. PLOS COMPUTATIONAL BIOLOGY, v. 16, n. 2 FEB 2020. Web of Science Citations: 0.
LIMA, MARILIA N. N.; CASSIANO, GUSTAVO C.; TOMAZ, KAIRA C. P.; SILVA, ARTHUR C.; SOUSA, BRUNA K. P.; FERREIRA, LETICIA T.; TAVELLA, TATYANA A.; CALIT, JULIANA; BARGIERI, DANIEL Y.; NEVES, BRUNO J.; COSTA, FABIO T. M.; ANDRADE, CAROLINA HORTA. Integrative Multi-Kinase Approach for the Identification of Potent Antiplasmodial Hits. FRONTIERS IN CHEMISTRY, v. 7, NOV 21 2019. Web of Science Citations: 0.
LIMA, MARILIA N. N.; NEVES, BRUNO J.; CASSIANO, GUSTAVO C.; GOMES, MARCELO N.; TOMAZ, KAIRA C. P.; FERREIRA, LETICIA T.; TAVELLA, TATYANA A.; CALIT, JULIANA; BARGIERI, DANIEL Y.; MURATOV, EUGENE N.; COSTA, FABIO T. M.; ANDRADE, CAROLINA HORTA. Chalcones as a basis for computer-aided drug design: innovative approaches to tackle. Future Medicinal Chemistry, v. 11, n. 20, p. 2635-2646, OCT 2019. Web of Science Citations: 0.
FERREIRA, LETICIA T.; VENANCIO, VINICIUS P.; KAWANO, TAILA; ABRAO, LAILAH C. C.; TAVELLA, TATYANA A.; ALMEIDA, LUDIMILA D.; PIRES, GABRIEL S.; BILSLAND, ELIZABETH; SUNNERHAGEN, PER; AZEVEDO, LUCIANA; TALCOTT, STEPHEN T.; MERTENS-TALCOTT, SUSANNE U.; COSTA, FABIO T. M. Chemical Genomic Profiling Unveils the in Vitro and in Vivo Antiplasmodial Mechanism of Acai (Euterpe oleracea Mart.) Polyphenols. ACS OMEGA, v. 4, n. 13, p. 15628-15635, SEP 24 2019. Web of Science Citations: 0.
BASTOS, MARCELE F.; ALBRECHT, LETUSA; GOMES, ANGELICA M.; LOPES, STEFANIE C. P.; VICENTE, CRISTINA P.; DE ALMEIDA, RODRIGO P. M.; CASSIANO, GUSTAVO C.; FONSECA, ROBERTO J. C.; WERNECK, CLAUDIO C.; PAVAO, MAURO S. G.; COSTA, FABIO T. M. A new heparan sulfate from the mollusk Nodipecten nodosus inhibits merozoite invasion and disrupts rosetting and cytoadherence of Plasmodium falciparum. Memórias do Instituto Oswaldo Cruz, v. 114, 2019. Web of Science Citations: 0.

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