Identifying protein kinase inhibitors as antimalarial agents using chemogenomic, bioinfomatics and phenotypic strategies: focus in Plasmodium vivax.

• Grant number: 15/20774-6
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): February 01, 2016
• Effective date (End): January 31, 2020
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal researcher: Fabio Trindade Maranhão Costa
• Grantee: Gustavo Capatti Cassiano
• Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 18/13571-0 - Identifying protein kinase inhibitors as antimalarial agents using chemogenomic, bioinfomatics and phenotypic strategies: focus in Plasmodium vivax., BE.EP.PD

Abstract

Malaria is one of the most important public health problems in tropical and subtropical areas, with approximately 200 million cases worldwide annually. In Brazil, P. vivax is the most prevalent species, accounting for around 85% of all cases, and reports of severe cases associated with P. vivax have been increasing in the last few years. In absence of an effective vaccine, rapid treatment is essential to malaria control. However, parasite resistance to currently available compounds highlights the urgent need for identifying new antimalarial therapies. In this context, the present project's main objective is to identify compounds against molecular targets whose inhibition may impair growth of sexual and asexual blood stages of P. vivax. At first, a comparative genomics strategy will be applied to select protein kinases that are essential for P. vivax and P. falciparum development, but absent or with low similarity in humans. Subsequently, using homology modelling and molecular docking, virtual screening will be performed in kinase inhibitor library (Biofocus). Compounds displaying in silico inhibitory potential will then be evaluated in functional assays. Initially, the compounds will be tested in in vitro assays with P. falciparum and in vivo using the experimental model of malaria P. chabaudi. Next, that compounds that display good inhibitory activity will be evaluated in ex vivo assays with P. vivax isolates from the Amazon. In conclusion, the present project could help to identify new antimalarial therapies, especially against vivax malaria.

Scientific publications

(10)

(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)

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.; ANDRADE, CAROLINA H. 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. Web of Science Citations: 0.

ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY, VOL 124: PROTEIN KINASES IN DRUG DISCOVERY. Web of Science Citations: 0.

ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY, VOL 124: PROTEIN KINASES IN DRUG DISCOVERY. Web of Science Citations: 0.

FERREIRA, LETICIA TIBURCIO; RODRIGUES, JULIANA; CASSIANO, GUSTAVO CAPATTI; TAVELLA, TATYANA ALMEIDA; PERALIS TOMAZ, KAIRA CRISTINA; BAIA-DA-SILVA, DJANE CLARYS; SOUZA, MACEJANE FERREIRA; DO NASCIMENTO LIMA, MARILIA NUNES; MOTTIN, MELINA; ALMEIDA, LUDIMILA DIAS; CALIT, JULIANA; SILVA DE BARROS PUCA, MARIA CAROLINA; MELO, GISELY CARDOSO; BARGIERI, DANIEL YOUSSEF; PINTO LOPES, STEFANIE COSTA; GUIMARAES LACERDA, MARCUS VINICIUS; BILSLAND, ELIZABETH; SUNNERHAGEN, PER; NEVES, BRUNO JUNIOR; ANDRADE, CAROLINA HORTA; LEMOS CRAVO, PEDRO VITOR; MARANHAO COSTA, FABIO TRINDADE. Computational Chemogenomics Drug Repositioning Strategy Enables the Discovery of Epirubicin as a New Repurposed Hit for Plasmodium falciparum and P. vivax. Antimicrobial Agents and Chemotherapy, v. 64, n. 9 SEP 2020. Web of Science Citations: 1.

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.

PIPPIONE, AGNESE C.; SAINAS, STEFANO; GOYAL, PARVEEN; FRITZSON, INGELA; CASSIANO, GUSTAVO C.; GIRAUDO, ALESSANDRO; GIORGIS, MARTA; TAVELLA, TATYANA A.; BAGNATI, RENZO; ROLANDO, BARBARA; CAING-CARLSSON, RHAWNIE; COSTA, FABIO T. M.; ANDRADE, CAROLINA HORTA; AL-KARADAGHI, SALAM; BOSCHI, DONATELLA; FRIEMANN, ROSMARIE; LOLLI, MARCO L. Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors: Synthesis, biological evaluation and X-ray structural studies. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 163, p. 266-280, FEB 1 2019. Web of Science Citations: 3.

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.

BITTENCOURT, NAJARA C.; LEITE, JULIANA A.; SILVA, ANA BEATRIZ I. E.; PIMENTA, TAMIRYS S.; SILVA-FILHO, JOAO LUIZ; CASSIANO, GUSTAVO C.; LOPES, STEFANIE C. P.; DOS-SANTOS, JOAO C. K.; BOURGARD, CATARINA; NAKAYA, HELDER I.; REVOREDO DA SILVA VENTURA, ANA MARIA; LACERDA, MARCUS V. G.; FERREIRA, MARCELO U.; MACHADO, RICARDO L. D.; ALBRECHT, LETUSA; COSTA, FABIO T. M. Genetic sequence characterization and naturally acquired immune response to Plasmodium vivax Rhoptry Neck Protein 2 (PvRON2). Malaria Journal, v. 17, OCT 31 2018. Web of Science Citations: 1.

LIMA, MARILIA N. N.; MELO-FILHO, CLEBER C.; CASSIANO, GUSTAVO C.; NEVES, BRUNO J.; ALVES, VINICIUS M.; BRAGA, RODOLPHO C.; CRAVO, PEDRO V. L.; MURATOV, EUGENE N.; CALIT, JULIANA; BARGIERI, DANIEL Y.; COSTA, FABIO T. M.; ANDRADE, CAROLINA H. QSAR-Driven Design and Discovery of Novel Compounds With Antiplasmodial and Transmission Blocking Activities. FRONTIERS IN PHARMACOLOGY, v. 9, MAR 6 2018. Web of Science Citations: 4.