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Structural biology and medicinal chemistry studies toward the discovery of new Plasmodium falciparum enolase inhibitors

Grant number: 16/09772-4
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): July 01, 2016
Effective date (End): February 28, 2018
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal Investigator:Rafael Victorio Carvalho Guido
Grantee:Guilherme Eduardo de Souza
Host 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


Malaria is a global public health problem with high mortality rates. In Brazil, malaria has a tremendous impact, where nearly 500,000 new cases per year are reported.1,2 In this scenario, new therapeutic alternatives with innovative mechanism of action are extremely needed. Glycolytic enzymes play important roles in Plasmodium biology. Intra-erythrocytic stages of P. falciparum lack the functional tricarboxylic acid cycle and rely solely on glycolysis for their energy requirements. Enolase (EC catalyses the reversible interconversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid and was found to be associated with nucleus, food vacuole, cytoskeleton, plasma membrane and invasion process, thereby exhibiting moonlighting functions. Therefore, Pf-eno is an attractive and validated target for antimalarial drug development. The aim of this project is to develop new promising compounds for the treatment of malaria by optimizing lead compounds, with appropriate activity and safety profiles. The lead compounds were discovered by screening the "Malaria Box" collection against P. falciparum enolase (Pfeno) enzyme in a standardized target-based assay. The screening identified 50 compounds as promising inhibitors of Pfeno. The evaluated IC50 values for the most potent compounds were in the low micromolar range. Among the top active compounds, the quinoline (MMV000570) and the benzoimidazole (MMV666607) derivatives look very attractive for further optimizations.State of the art methods and strategies in structural molecular biology and medicinal chemistry will be employed in the design of improved leads through the integration of organic synthesis, SAR studies and structure-based drug design approaches. The compounds will be evaluated in standard biological assays against the target enzyme and to guide the design of new derivatives, crystal structures of ligand-protein complexes will be obtained. The Sao Carlos Institute of Physics has a world renowned structural biology and medicinal chemistry program which has been strengthened by the establishment of the Center for Research and Innovation in Biodiversity and Drug Discovery, providing state of the art facilities for the characterization of proteins and their binding partners. Our facilities are therefore well equipped to support all steps of this proposal. (AU)

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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, . (16/09772-4, 13/07600-3, 15/18192-9)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
SOUZA, Guilherme Eduardo de. Discovery of hydrazinobenzimidazole derivatives as Plasmodium falciparum inhibitors: Organic Synthesis, Biological Activity and Structure-Activity Relationships. 2018. Master's Dissertation - Universidade de São Paulo (USP). Instituto de Física de São Carlos (IFSC/BT) São Carlos.

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