Discovery of inhibitors from Brazilian Savana plants as lead compound candidates for Malaria

• Grant number: 21/03977-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: April 01, 2022
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Rafael Victorio Carvalho Guido
• Grantee: Igor Mota Rodrigues de Moura
• 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
• Associated scholarship(s): 23/10879-1 - Determining the mode of action of peptide-like molecules with pronounced antiplasmodial activity against Plasmodium falciparum resistant strains, BE.EP.DR

Abstract

Malaria is a lethal parasitosis, worldwide prevalence, and despite investments in the discovery of new drug candidates, a high mortality rate is still observed. In the search for new candidates as antimalarial drugs, the modulation of the glycolytic pathway has been investigated as an attractive target to inhibit the development of the parasite and the fight infection. The enolase enzyme from Plasmodium falciparum (Pfeno) is an attractive target of the parasite's glycolytic pathway that catalyzes the conversion of 2-fostoglycerate (2PG) into phosphoenolpyruvate (PEP). This enzyme is related to other important cellular functions ("moonlighting" functions, non-glycolytic functions), as well, due to the different biological compartments where it is localized. Our group, CIBFar/CEPID, determined the 3D crystallographic structure of Pfeno alone and in complex with inhibitors. These crystallographic data have revealed critical structural differences in comparison with the human homologue that support the search for new selective inhibitors. In light of the success of antiMalarial drugs from Natural Products (NP) and that the Savana (Cerrado) is a promising source of global biodiversity, this proposal aims to investigate bioactive compounds from this important Brazilian biome against the P. falciparum. Some plant species were selected for screening against both the enzyme and the whole parasite based on the antiplasmodial activities reported. For example, fruits and bark extracts of the stem of Qualea grandiflora (Vochysiaceae) were previously investigated in a collaborative research work between CIBFar-CEPID and LaBiOrg - UFG/RC. This study indicated that the extract showed potent in vitro inhibitory activity against P. falciparum (IC50 values between 1.2 ng/mL and 7 ng/mL) and substantial in vivo activity (100% reduction in parasitemia at 100 mg/kg in the fifth day postinfection by P. berghei). The most potent extracts will be subjected to experiments in hyphenated analytical techniques using high resolution mass spectrometry (CLUE-EM/EM) and the phytochemical investigation will be carried out using HPLC-DAD guided by 1H NMR. The isolated compounds will be investigated against both the Pfeno and P. falciparum strains (sensitive and resistant), as well as will have their cytotoxicity and selectivity assessed. The isolated compounds that show significant inhibition of both the enzyme (IC50Pfeno < 1 µM) and the parasite growth (IC50Pf < 1 µM) and promising selectivity index (SI > 10) will be selected for in vivo studies to assess the efficacy in an animal model and confirm the discovery of new lead candidates for Malaria. (AU)

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)

BARBOSA, CAMILA S.; AHMAD, ANEES; MALUF, SARAH EL CHAMY; MOURA, IGOR M. R.; SOUZA, GUILHERME E.; GUERRA, GIOVANNA A. H.; BARROS, ROBERTO R. MORAES; GAZARINI, MARCOS L.; AGUIAR, ANNA C. C.; BURTOLOSO, ANTONIO C. B.; et al. Synthesis, Structure-Activity Relationships, and Parasitological Profiling of Brussonol Derivatives as New Plasmodium falciparum Inhibitors. PHARMACEUTICALS, v. 15, n. 7, p. 21-pg., 2022-07-01. (13/07600-3, 21/03977-1, 20/14429-2, 19/17721-9, 19/19708-0, 20/12904-5, 18/06219-8, 15/20084-0, 18/07287-7, 13/18009-4, 21/14319-5)