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

• Grant number: 17/18611-7
• Support Opportunities: Research Projects - Thematic Grants
• Start date: September 01, 2018
• End date: August 31, 2025
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Fabio Trindade Maranhão Costa
• Grantee: Fabio Trindade Maranhão Costa
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• City of the host institution: Campinas
• Associated researchers: Aline Mara dos Santos ; Carolina Horta Andrade ; Daniel Youssef Bargieri ; Elizabeth Bilsland ; Leonardo José de Moura Carvalho ; Letícia Tiburcio Ferreira ; 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 research grant(s): 24/02019-5 - Study of epigenetic mechanisms related to relapses in vivax malaria, AP.R; 20/05369-6 - Artificial inteligence driven drug repositioning strategy for COVID-19, AP.R
• Associated scholarship(s): 24/07765-7 - Identification of cellular subpopulations in recurrent hypnozoite infections in vivax malaria patients (HYPNOPRINT), BP.TT; 24/05218-9 - Assessment of the humoral immune response against Plasmodium vivax antigens in patients with malaria relapses., BP.IC; 23/12812-1 - Original antimicrobial compounds as new therapeutic alternatives to control chemoresistant Plasmodium spp: validation of multistage antimalarial activity and investigation of mode of action, BP.DR; + associated scholarships 23/08454-2 - Characterization of recurrent episodes of Vivax Malaria and identification of predictive biomarkers for disease relapse, BP.DD; 22/12894-5 - Comparative investigation of Plasmodium spp. biology derived from bone marrow and peripheral blood, BP.PD; 23/07805-6 - Identification of predictive metabolic signatures for recurrent infections by hypnozoites in patients with vivax malaria (HIPNOPRINT), BP.TT; 23/01208-6 - Development of new tools for searching and validating molecular targets for therapy against Plasmodium vivax, BP.TT; 22/02080-0 - Host-parasite interactions during infection in the hematopoietic niche in malaria: in vitro assays for the evaluation of Plasmodium reticulocyte, BP.IC; 21/14014-0 - Comparative study of Plasmodium vivax niches with emphasis on bone marrow and peripheral blood and their roles in the infection and pathology of this parasite, BP.PD; 21/11543-1 - Compounds with multistage antimalarial potential: evaluation of activity against Plasmodium falciparum in vitro, BP.IC; 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; 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

(29)

(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.; et al. Keras R-CNN: library for cell detection in biological images using deep neural networks. BMC Bioinformatics, v. 21, n. 1, JUL 11 2020. (17/18611-7)

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. (17/02353-9, 17/18611-7, 15/20774-6, 12/16525-2)

MAHAMBO, EMANUEL T.; UWAMARIYA, COLORES; MIAH, MASUM; CLEMENTINO, LEANDRO DA COSTA; ALVAREZ, LUIS CARLOS SALAZAR; MEZTLER, GABRIELA PAULA DI SANTO; TRYBALA, EDWARD; SAID, JOANNA; WIESKE, LIANNE H. E.; WARD, JAS S.; et al. Crotofolane Diterpenoids and Other Constituents Isolated from Croton kilwae. Journal of Natural Products, v. 86, n. 2, p. 10-pg., 2023-02-24. (17/18611-7)

BORBA, JOYCE V. B.; DE AZEVEDO, BEATRIZ ROSA; FERREIRA, LARISSA A.; RIMOLDI, ALINE; ALVAREZ, LUIS C. SALAZAR; CALIT, JULIANA; BARGIERI, DANIEL Y.; COSTA, FABIO T. M.; ANDRADE, CAROLINA HORTA. Transcriptomics-Guided In Silico Drug Repurposing: Identifying New Candidates with Dual-Stage Antiplasmodial Activity. ACS OMEGA, v. 8, n. 37, p. 7-pg., 2023-09-05. (18/24878-9, 19/21854-4, 21/06769-0, 17/18611-7)

ALBRECHT, LETUSA; LOPES, STEFANIE C. P.; IUNG ENEMBRECK DA SILVA, ANA BEATRIZ; BARBOSA, VANESSA; ALMEIDA, RODRIGO P.; SIQUEIRA, ANDRE M.; LEITE, JULIANA ALMEIDA; BITTENCOURT, NAJARA C.; DOS SANTOS, HELLEN GEREMIAS; BOURGARD, CATARINA; et al. Rosettes integrity protects Plasmodium vivax of being phagocytized. SCIENTIFIC REPORTS, v. 10, n. 1, OCT 7 2020. (13/20509-5, 12/16525-2, 13/25807-4, 17/18611-7)

ANA PAULA SCHAPPO; NAJARA C BITTENCOURT; LETICIA P BERTOLLA; SOFIA FORCELLINI; ANA BEATRIZ IUNG ENEMBRECK DA SILVA; HELLEN GEREMIAS DOS SANTOS; JOÃO HENRIQUE GERVÁSIO; MARCUS VG LACERDA; STEFANIE CP LOPES; FABIO TM COSTA; et al. Antigenicity and adhesiveness of a Plasmodium vivax VIR-E protein from Brazilian isolates. Memórias do Instituto Oswaldo Cruz, v. 116, 2022-02-04. (17/18611-7)

NYIRENDA, JAMES; HARDY, OLYMPIA M.; SILVA FILHO, JOAO DA; HERDER, VANESSA; ATTIPA, CHARALAMPOS; NDOVI, CHARLES; SIWOMBO, MEMORY; NAMALIMA, TAKONDWA REX; SUWEDI, LETICIA; ILIA, GEORGIOS; et al. Spatially resolved single-cell atlas unveils a distinct cellular signature of fatal lung COVID-19 in a Malawian population. Nature Medicine, v. N/A, p. 42-pg., 2024-11-20. (16/12855-9, 20/05369-6, 17/18611-7)

VOLPE-ZANUTTO, FABIANA; FERREIRA, LETICIA TIBURCIO; PERMANA, ANDI DIAN; KIRKBY, MELISSA; PAREDES, ALEJANDRO J.; VORA, LALITKUMAR K.; BONFANTI, AMANDA P.; CHARLIE-SILVA, IVES; RAPOSO, CATARINA; FIGUEIREDO, MARIANA C.; et al. Artemether and lumefantrine dissolving microneedle patches with improved pharmacokinetic performance and antimalarial efficacy in mice infected with Plasmodium yoelii. JOURNAL OF CONTROLLED RELEASE, v. 333, p. 298-315, MAY 10 2021. (19/02171-3, 16/18384-8, 14/16008-3, 17/18611-7)

YAKUBU, MICHAEL N.; MWANGI, VICTOR I.; ALMEIDA, ANNE C. G.; LIRA, EMANUELLE; ADRIAO, ASENATE A. X.; DOS SANTOS, GABRIEL F.; LIMA, GESIANE S.; MACHADO, LUCAS S.; KOOLEN, HECTOR H. F.; GUIMARAES, TIAGO P.; et al. Metabolic disruptions in P. vivax malaria: Insights from four antimalarial treatment regimens. Acta Tropica, v. 268, p. 11-pg., 2025-07-11. (22/12894-5, 17/18611-7, 21/04632-8)

FERREIRA, LETICIA TIBURCIO; BORBA, JOYCE V. B.; MOREIRA-FILHO, JOSE TEOFILO; RIMOLDI, ALINE; ANDRADE, CAROLINA HORTA; COSTA, FABIO TRINDADE MARANHAO. QSAR-Based Virtual Screening of Natural Products Database for Identification of Potent Antimalarial Hits. BIOMOLECULES, v. 11, n. 3, MAR 2021. (19/21854-4, 19/02171-3, 20/02158-4, 17/18611-7)

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.; et al. 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. (17/02031-1, 13/13119-6, 17/02353-9, 17/18611-7, 12/16525-2, 18/24878-9)

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; et al. 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. (15/03553-6, 17/01986-8, 17/18611-7, 17/50400-6, 18/07007-4)

DA VEIGA, GISELE TATIANE SOARES; DONASSOLO, RAFAEL AMARAL; FORCELLINI, SOFIA; FERRABOLI, JULIA WEBER; KUJBIDA JUNIOR, MARIO ANTONIO; NISIMURA, LINDICE MITIE; BASSAI, LETICIA WERZEL; KESSLER, RAFAEL LUIS; SERPELONI, MARIANA; BITTENCOURT, NAJARA CARNEIRO; et al. Exploring the naturally acquired response to Pvs47 gametocyte antigen. FRONTIERS IN IMMUNOLOGY, v. 15, p. 16-pg., 2024-10-10. (17/18611-7)

YAKUBU, MICHAEL N.; MWANGI, VICTOR I.; NETTO, REBECA L. A.; ALECRIM, MARIA G. C.; ALVES, JESSICA R. S.; ALMEIDA, ANNE C. G.; SANTOS, GABRIEL F.; LIMA, GESIANE S.; MACHADO, LUCAS S.; KOOLEN, HECTOR H. F.; et al. Host metabolomic responses in recurrent P. vivax malaria. SCIENTIFIC REPORTS, v. 14, n. 1, p. 13-pg., 2024-03-27. (23/01208-6, 21/14014-0, 17/18611-7, 21/04632-8)

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.; et al. Integrative Multi-Kinase Approach for the Identification of Potent Antiplasmodial Hits. FRONTIERS IN CHEMISTRY, v. 7, NOV 21 2019. (18/05926-2, 13/13119-6, 18/07007-4, 17/02353-9, 17/18611-7, 12/16525-2, 18/24878-9, 15/20774-6)

DA SILVA FILHO, JOAO; HERDER, VANESSA; GIBBINS, MATTHEW P.; DOS REIS, MONIQUE FREIRE; MELO, GISELY CARDOSO; HALEY, MICHAEL J.; JUDICE, CARLA CRISTINA; VAL, FERNANDO FONSECA ALMEIDA; BORBA, MAYLA; TAVELLA, TATYANA ALMEIDA; et al. A spatially resolved single-cell lung atlas integrated with clinical and blood signatures distinguishes COVID-19 disease trajectories. Science Translational Medicine, v. 16, n. 764, p. 18-pg., 2024-09-11. (17/18611-7)

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; et al. Platelet disturbances correlate with endothelial cell activation in uncomplicatedPlasmodium vivaxmalaria. PLoS Neglected Tropical Diseases, v. 14, n. 7, JUL 2020. (16/12855-9, 17/18611-7, 12/16525-2)

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. (19/01578-2, 16/12855-9, 17/18611-7)

CAMILA FABBRI; ALEXANDRE OLIVEIRA TRINDADE; FRANCYS SAYARA ANDRADE; MACEJANE FERREIRA DE SOUZA; CLAUDIA MARÍA RÍOS-VELÁSQUEZ; MARCUS VINICIUS GUIMARÃES DE LACERDA; WUELTON MARCELO MONTEIRO; FABIO TRINDADE MARANHÃO COSTA; ROGERIO AMINO; STEFANIE COSTA PINTO LOPES. Transmission-blocking compound candidates against Plasmodium vivax using P. berghei as an initial screening. Memórias do Instituto Oswaldo Cruz, v. 116, 2021-02-08. (17/18611-7)

CASSIANO, G. C.; TAVELLA, T. A.; NASCIMENTO, M. N.; RODRIGUES, D. A.; CRAVO, P. V. L.; ANDRADE, CAROLINA HORTA; MARANHAO COSTA, FABIO TRINDADE; DONEV, R. Targeting malaria protein kinases. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY, VOL 124: PROTEIN KINASES IN DRUG DISCOVERY, v. 124, p. 50-pg., 2021-01-01. (17/18611-7, 19/27626-3, 15/20774-6)

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.; et al. Integrative Multi-Kinase Approach for the Identification of Potent Antiplasmodial Hits. RONTIERS IN CHEMISTR, v. 7, p. 14-pg., 2019-11-21. (17/02353-9, 18/05926-2, 13/13119-6, 18/24878-9, 18/07007-4, 15/20774-6, 12/16525-2, 17/18611-7)

VERDE BASTOS BORBA, JOYCE VILLA; SILVA, ARTHUR CARVALHO; NASCIMENTO LIMA, MARILIA NUNES; MENDONCA, SABRINA SILVA; FURNHAM, NICHOLAS; MARANHAO COSTA, FABIO TRINDADE; ANDRADE, CAROLINA HORTA; DONEV, R. Chemogenomics and bioinformatics approaches for prioritizing kinases as drug targets for neglected tropical diseases. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY, VOL 124: PROTEIN KINASES IN DRUG DISCOVERY, v. 124, p. 37-pg., 2021-01-01. (17/18611-7, 19/21854-4)

FERREIRA, LETICIA TIBURCIO; CASSIANO, GUSTAVO CAPATTI; ALVAREZ, LUIS CARLOS SALAZAR; OKOMBO, JOHN; CALIT, JULIANA; FONTINHA, DIANA; GIL-ITURBE, EVA; COYLE, RACHAEL; ANDRADE, CAROLINA HORTA; SUNNERHAGEN, PER; et al. A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants. PLOS PATHOGENS, v. 20, n. 10, p. 25-pg., 2024-10-01. (18/24878-9, 19/02171-3, 21/06769-0, 21/13809-9, 17/18611-7)

SALAZAR ALVAREZ, LUIS CARLOS; VERA LIZCANO, OMAIRA; DA SILVA BARROS, DAYANNE KAMYLLA ALVES; BAIA-DA-SILVA, DJANE CLARYS; MONTEIRO, WUELTON MARCELO; PIMENTA, PAULO FILEMON PAOLLUCI; DE LACERDA, MARCUS VINICIUS GUIMARAES; COSTA, FABIO TRINDADE MARANHAO; LOPES, STEFANIE COSTA PINTO. Plasmodium vivax Gametocytes Adherence to Bone Marrow Endothelial Cells. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, JUN 24 2021. (17/18611-7)

PUHL, ANA C.; FRITCH, ETHAN J.; LANE, THOMAS R.; TSE, V, LONGPING; YOUNT, BOYD L.; SACRAMENTO, CAROLINA Q.; FINTELMAN-RODRIGUES, NATALIA; TAVELLA, TATYANA ALMEIDA; COSTA, FABIO TRINDADE MARANHAO; WESTON, STUART; et al. Repurposing the Ebola and Marburg Virus Inhibitors Tilorone, Quinacrine, and Pyronaridine: In Vitro Activity against SARS-CoV-2 and Potential Mechanisms. ACS OMEGA, v. 6, n. 11, p. 7454-7468, MAR 23 2021. (19/27626-3, 17/18611-7, 20/05369-6)

BOURGARD, CATARINA; LOPES, STEFANIE C. P.; LACERDA, MARCUS V. G.; ALBRECHT, LETUSA; COSTA, FABIO T. M.. A suitable RNA preparation methodology for whole transcriptome shotgun sequencing harvested from Plasmodium vivax-infected patients. SCIENTIFIC REPORTS, v. 11, n. 1, MAR 3 2021. (12/16525-2, 13/20509-5, 17/18611-7)

LIMA, MARILIA N. N.; BORBA, JOYCE V. B.; CASSIANO, GUSTAVO C.; MOTTIN, MELINA; MENDONCA, SABRINA S.; SILVA, ARTHUR C.; TOMAZ, KAIRA C. P.; CALIT, JULIANA; BARGIERI, DANIEL Y.; COSTA, FABIO T. M.; et al. Artificial Intelligence Applied to the Rapid Identification of New Antimalarial Candidates with Dual-Stage Activity. CHEMMEDCHEM, v. 16, n. 7, p. 1093-1103, APR 8 2021. (15/20774-6, 13/13119-6, 17/18611-7, 18/24878-9, 18/07007-4, 19/21854-4)

SILVA-FILHO, JOAO L.; DOS-SANTOS, JOAO C. K.; JUDICE, CARLA; BERALDI, DARIO; VENUGOPAL, KANNAN; LIMA, DIOGENES; NAKAYA, I, HELDER; DE PAULA, V, ERICH; LOPES, STEFANIE C. P.; LACERDA, MARCUS V. G.; et al. Total parasite biomass but not peripheral parasitaemia is associated with endothelial and haematological perturbations in Plasmodium vivax patients. eLIFE, v. 10, SEP 29 2021. (16/12855-9, 19/01578-2, 17/18611-7)

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.; et al. 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. (17/18611-7, 12/16525-2, 10/18571-6, 15/20774-6)