Discovery and development of Antimalarial Drugs: Structural Biology, Medicinal Chemistry and Parasitology

• Grant number: 15/18192-9
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): January 01, 2016
• Effective date (End): December 31, 2018
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal researcher: Glaucius Oliva
• Grantee: Anna Caroline Campos Aguiar
• Home Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated research grant: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery, AP.CEPID

Abstract

Malaria, caused by protozoa of the genus Plasmodium, is one of the main public health problems worldwide. The disease occurs in 109 countries and is endemic in tropical and subtropical regions of Africa, Southeast Asia and Latin America. Virtually, half the world's population (3.3 billion people) is exposed to malaria transmission. In 2013, 198 million cases and 584,000 deaths were reported, most of them in Africa (WHO, 2014). The emergence of drug resistance cases boosts the search for new molecular targets and the development of chemotherapeutic agents against the disease.The research project aims at (i) the elucidation of the three dimensional structure of the phosphatidylinositol-4-OH kinase (PI4K), an important enzyme in the metabolism of Plasmodium; (ii) the development of in vivo and in vitro assays for screening compounds as antimalarial candidate and (iii) the discovery and development of new bioactive compounds as drug candidates for malaria. To this end, integrated studies in structural molecular biology, enzyme kinetics, cell biology, parasitology and pharmacology will be employed. Phosphatidylinositol-4-OH kinase (PI4K), a ubiquitous eukaryotic enzyme, is responsible for phosphorylation of lipids and participates in the regulation of intracellular signaling and transport vesicles. The enzyme was recently described as essential in all cell cycle stages of the parasite. Furthermore, PI4K has significant differences related to the human homologous protein, thereby the enzyme is an attractive molecular target for the development of new antimalarials. The project will be developed in Laboratory of Medicinal and Computer Chemistry - LQMC, held at the Center for Innovation in Biodiversity and Drugs - CIBFar-CEPID in the São Carlos Institute of Physics, USP. The LQMC-CIBFar laboratories have complete infrastructure to accomplish all the steps proposed in this research project.

Scientific publications

(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)

DE SOUZA, GUILHERME EDUARDO; BUENO, RENATA VIEIRA; DE SOUZA, JULIANA OLIVEIRA; ZANINI, CAMILA LIMA; CRUZ, FABIO CARDOSO; OLIVA, GLAUCIUS; CARVALHO GUIDO, RAFAEL VICTORIO; CAMPOS AGUIAR, ANNA CAROLINE. Antiplasmodial profile of selected compounds from Malaria Box: in vitro evaluation, speed of action and drug combination studies. Malaria Journal, v. 18, n. 1 DEC 30 2019. Web of Science Citations: 0.

DE GODOY, ANDRE SCHUTZER; FERNANDES, RAFAELA SACHETTO; CAMPOS AGUIAR, ANNA CAROLINE; BUENO, RENATA VIEIRA; DE MORAES ROSO MESQUITA, NATHALYA CRISTINA; CARVALHO GUIDO, RAFAEL VICTORIO; OLIVA, GLAUCIUS. Structural and mechanistic insight from antiviral and antiparasitic enzyme drug targets for tropical infectious diseases. CURRENT OPINION IN STRUCTURAL BIOLOGY, v. 59, p. 65-72, DEC 2019. Web of Science Citations: 0.

CAMPOS AGUIAR, ANNA CAROLINE; PANCIERA, MICHELE; SIMAO DOS SANTOS, ERIC FRANCISCO; SINGH, MANEESH KUMAR; GARCIA, MARIANA LOPES; DE SOUZA, GUILHERME EDUARDO; NAKABASHI, MYNA; COSTA, JOSE LUIZ; GARCIA, CELIA R. S.; OLIVA, GLAUCIUS; DUARTE CORREIA, CARLOS ROQUE; CARVALHO GUIDO, RAFAEL VICTORIO. Discovery of Marinoquinolines as Potent and Fast-Acting Plasmodium falciparum Inhibitors with in Vivo Activity. Journal of Medicinal Chemistry, v. 61, n. 13, p. 5547-5568, JUL 12 2018. Web of Science Citations: 7.