Discovery of Plasmodium falciparum inhibitors from Cerrado plants as lead compounds candidates for malaria: integrated studies of ultra-efficient chromatography, spectroscopy, and biological assays

• Grant number: 20/12904-5
• Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants
• Start date: June 01, 2021
• End date: May 31, 2023
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Rafael Victorio Carvalho Guido
• Grantee: Rafael Victorio Carvalho Guido
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated researchers: Lorena Ramos Freitas de Sousa

Abstract

Malaria is a lethal parasitosis, worldwide prevalent, and despite investments in the search for new drugs, a high mortality rate is still observed. In the search for new candidates for antimalarial drug discovery, glycolytic pathway modulation has been explored as target to inhibit parasite development and fight infection. Enolase (Pfeno) is an attractive target of the parasite glycolytic pathway, which catalyzes the conversion of 2-phosphoglycerate (2PG) to phosphoenolpyruvate (PEP). Moreover, the enzyme is associated with other important cellular functions (moonlighting functions, non-glycolytic functions) due to the different biological compartments in which Pfeno is found. Recently our group (CIBFaR-CEPID) determined the 3D crystallographic structure of Pfeno along with its enzymatic complexes. The 3D structures indicated differences related to the homologous human enzyme that allow the search for new selective inhibitors. Given the success of antimalarial drugs from natural products (PNs) and that the Cerrado is a hotspot of world biodiversity, this proposal aims to investigate bioactive compounds against malaria from plants of this biome. Some plant species were selected for screening based on reported antiplasmodial activities of the species or genus of these plants. Among these, the fractions of fruits and bark of Qualea grandiflora stem (Vochysiaceae) were previously investigated, in collaboration between CIBFar-CEPID and LaBiOrg - UFG / RC, with promising in vitro activity against Plasmodium falciparum cultures (IC50 values between 1.2 ng / mL and 7.0 ng / mL), in vivo (100% reduction in parasitemia after the fifth day of P. berghei infection), and the identification of 32 compounds. LaBiOrg - UFG / RC has a significant collection of Cerrado plant extracts that will be investigated in this proposal. The extracts will be evaluated against Pfeno and the most promising extracts will be submitted to experiments in hyphenated analytical techniques including high resolution mass spectrometry (CLUE-MS / MS). The CLUE-MS / MS detection limit allows the identification of minor compounds that may be related to the biological activity. The phytochemical investigation will be performed using 1H NMR-guided HPLC-DAD. The isolated compounds will be investigated against Pfeno and P. falciparum strains (3D7 and K1), as well as cytotoxicity and selectivity assessed. Compounds with significant inhibition of enzyme and parasite growth will be selected as lead compounds candidates. (AU)

Scientific publications

(17)

(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)

PINA, JEFERSON RODRIGO SOUZA; SILVA-SILVA, JOAO VICTOR; CARVALHO, JOSIWANDER MIRANDA; BITENCOURT, HERIBERTO RODRIGUES; WATANABE, LUCIANO ALMEIDA; FERNANDES, JUAN MATHEUS PEREIRA; DE SOUZA, GUILHERME EDUARDO; AGUIAR, ANNA CAROLINE CAMPOS; GUIDO, RAFAEL VICTORIO CARVALHO; ALMEIDA-SOUZA, FERNANDO; et al. Antiprotozoal and Antibacterial Activity of Ravenelin, a Xanthone Isolated from the Endophytic Fungus Exserohilum rostratum. Molecules, v. 26, n. 11, JUN 2021. (20/12904-5, 13/07600-3)

COSTA, RENNA K. E.; BRANCAGLION, GUILHERME A.; PINHEIRO, MATHEUS P.; ADAMOSKI, DOUGLAS; DA SILVA, BIANCA N.; NEGRAO, CYRO Z. DE V.; GONCALVES, KALIANDRA DE A.; RODRIGUES, CAMILA T.; AMBROSIO, ANDRE L. B.; GUIDO, RAFAEL V. C.; et al. Discovery of aminothiazole derivatives as a chemical scaffold for glutaminase inhibition. RESULTS IN CHEMISTRY, v. 5, p. 17-pg., 2023-02-17. (13/07600-3, 16/09077-4, 21/13736-1, 14/26378-2, 19/16351-3, 20/12904-5, 21/06661-5, 14/15968-3)

INACIO, MARIELLE CASCAES; PAZ, TIAGO ANTUNES; WIJERATNE, E. M. KITHSIRI; GUNAHERATH, G. M. KAMAL B.; GUIDO, RAFAEL V. C.; GUNATILAKA, A. A. LESLIE. Antimicrobial activity of some celastroloids and their derivatives. MEDICINAL CHEMISTRY RESEARCH, v. 31, n. 9, p. 12-pg., 2022-07-13. (20/12904-5, 14/19362-2, 18/00143-0, 13/07600-3)

DE AMORIM, MARCELO R.; PAZ, TIAGO A.; PINTO, LUCIANO DA S.; HILARIO, FELIPE; ZANINI, CAMILA L.; AGUIAR, ANNA CAROLINE C.; SILVA, DEBORA E. S.; FURLAN, MAYSA; GUIDO, RAFAEL V. C.; BAUAB, TAIS M.; et al. New Isoquinoline Alkaloids from Paraphaeosphaeria sporulosa F03, a Fungal Endophyte Isolated from Paepalanthus planifolius. Planta Medica, v. N/A, p. 10-pg., 2022-01-19. (20/12904-5, 16/17711-5, 15/11058-5, 13/07600-3, 15/04899-3)

XIE, STANLEY C.; METCALFE, RILEY D.; MIZUTANI, HIROTAKE; PUHALOVICH, TANYA; HANSSEN, ERIC; MORTON, CRAIG J.; DU, YAWEI; DOGOVSKI, CON; HUANG, SHIH-CHUNG; CIAVARRI, JEFFREY; et al. Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 118, n. 39, SEP 28 2021. (13/07600-3, 20/12904-5)

DE AMORIM, MARCELO R.; BARBOSA, CAMILA DE S.; PAZ, TIAGO A.; IOCA, LAURA P.; NICACIO, KAREN J.; DE OLIVEIRA, LUCIANNE F. P.; GOULART, MIRIAN O.; PAULINO, JULIA M.; DA CRUZ, MATEUS O.; FERREIRA, ANTONIO G.; et al. Polyketide- and Terpenoid-Derived Metabolites Produced by a Marine-Derived Fungus, Peroneutypa sp.. Journal of Natural Products, v. 86, n. 6, p. 11-pg., 2023-06-08. (19/17721-9, 16/05133-7, 15/01017-0, 20/12904-5, 20/01229-5)

BITENCOURT, NATALIA VITORIA; RIGHETTO, GABRIELA MARINHO; CAMARGO, ILANA LOPES BARATELLA CUNHA; DE GODOY, MARIANA ORTIZ; GUIDO, RAFAEL VICTORIO CARVALHO; OLIVA, GLAUCIUS; SANTOS-FILHO, NORIVAL ALVES; CILLI, EDUARDO MAFFUD. Effects of Dimerization, Dendrimerization, and Chirality in p-BthTX-I Peptide Analogs on the Antibacterial Activity and Enzymatic Inhibition of the SARS-CoV-2 PLpro Protein. PHARMACEUTICS, v. 15, n. 2, p. 17-pg., 2023-02-01. (13/07600-3, 14/50926-0, 20/12904-5)

IRABUENA, CAMILA; SCARONE, LAURA; EDUARDO DE SOUZA, GUILHERME; CAMPOS AGUIAR, ANNA CAROLINE; ROSSI MENDES, GIOVANA; CARVALHO GUIDO, RAFAEL VICTORIO; SERRA, GLORIA. ynthesis and antiplasmodial assessment of nitazoxanide and analogs as new antimalarial candidate. MEDICINAL CHEMISTRY RESEARCH, v. 31, n. 3, p. 426-435, MAR 2022. (13/07600-3, 18/07287-7, 20/12904-5)

SILVA-SILVA, JOAO VICTOR; MORAGAS-TELLIS, CARLA J.; CHAGAS, MARIA S. S.; SOUZA, PAULO VICTOR R.; MOREIRA, DAVYSON L.; DE SOUZA, CELESTE S. F.; TEIXEIRA, KEROLAIN F.; CENCI, ARTHUR R.; DE OLIVEIRA, ALDO S.; ALMEIDA-SOUZA, FERNANDO; et al. Carajurin: a anthocyanidin from Arrabidaea chica as a potential biological marker of antileishmanial activity. BIOMEDICINE & PHARMACOTHERAPY, v. 141, SEP 2021. (13/07600-3, 20/12904-5)

MOTTIN, MELINA; SOUSA, BRUNA KATIELE DE PAULA; MESQUITA, NATHALYA CRISTINA DE MORAES ROSO; DE OLIVEIRA, KETLLYN IRENE ZAGATO; NOSKE, GABRIELA DIAS; SARTORI, GERALDO RODRIGUES; ALBUQUERQUE, ALINE DE OLIVEIRA; URBINA, FABIO; PUHL, ANA C.; MOREIRA-FILHO, JOSE TEOFILO; et al. Discovery of New Zika Protease and Polymerase Inhibitors through the Open Science Collaboration Project OpenZika. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 62, n. 24, p. 19-pg., 2022-10-14. (20/12904-5, 13/07600-3)

CORTOPASSI, WILIAN A.; GUNDERSON, EMMA; ANNUNCIATO, YASMIN; SILVA, ANTONY. E. S.; FERREIRA, AMALIA DOS SANTOS; TELES, CAROLINA BIONI GARCIA; PIMENTEL, ANDRE S.; RAMAMOORTHI, ROOPA; GAZARINI, MARCOS L.; MENEGHETTI, MARIO R.; et al. Fighting Plasmodium chloroquine resistance with acetylenic chloroquine analogues. INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE, v. 20, p. 8-pg., 2022-11-11. (13/07600-3, 19/19708-0, 20/12904-5)

MENDES, LEIA DA C.; DANTAS, THAIS B. VIEIRA; SEVERINO, RICHELE P.; DA SILVA, LARISSA RAMOS G.; DE SOUZA, DULCE H. F.; CASS, QUEZIA B.; RAMALHO, SUELEM D.; VIEIRA, PAULO C.; DE SOUZA, GUILHERME E.; GUIDO, RAFAEL V. C.; et al. Using molecular networking and docking to explore arginase inhibitors among Drimys brasiliensis chemical constituents. MEDICINAL CHEMISTRY RESEARCH, v. 32, n. 10, p. 11-pg., 2023-07-24. (13/07600-3, 20/12904-5)

DE VRIES, LAURA E.; JANSEN, PATRICK A. M.; BARCELO, CATALINA; MUNRO, JUSTIN; VERHOEF, JULIE M. J.; PASAJE, CHARISSE FLERIDA A.; RUBIANO, KELLY; STRIEPEN, JOSEFINE; ABLA, NADA; BERNING, LUUK; et al. Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183. NATURE COMMUNICATIONS, v. 13, n. 1, p. 16-pg., 2022-04-20. (13/07600-3, 19/19708-0, 20/12904-5)

MOTTIN, MELINA; CAESAR, LINDSAY K.; BRODSKY, DAVID; MESQUITA, NATHALYA C. M. R.; DE OLIVEIRA, KETLLYN ZAGATO; NOSKE, GABRIELA DIAS; SOUSA, BRUNA K. P.; RAMOS, PAULO R. P. S.; JARMER, HANNAH; LOH, BONNIE; et al. Chalcones from Angelica keiskei (ashitaba) inhibit key Zika virus replication proteins. BIOORGANIC CHEMISTRY, v. 120, p. 12-pg., 2022-02-03. (13/07600-3, 16/17153-2, 18/19574-0, 20/12904-5)

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)

RAMOS, PAULO RICARDO PIMENTA DA SILVA; MOTTIN, MELINA; LIMA, CAROLINE SPRENGEL; ASSIS, LETICIA R.; DE OLIVEIRA, KETLLYN ZAGATO; MESQUITA, NATHALYA CRISTINA DE MORAES ROSO; CASSANI, NATASHA MARQUES; SANTOS, IGOR ANDRADE; BORBA, JOYCE VILLA VERDE BASTOS; FIAIA COSTA, VINICIUS ALEXANDRE; et al. Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches. PHARMACEUTICALS, v. 15, n. 12, p. 17-pg., 2022-12-01. (14/18330-0, 19/01762-8, 13/07600-3, 18/15083-2, 20/12904-5)

MOREIRA, NATAILIA M.; DE MIRANDA, INGRID T.; DOS SANTOS, JHONATHAN R. N.; OPATZ, TILL; OLIVA, GLAUCIUS; GUIDO, RAFAEL V. C.; CORREA, ARLENE G.. Copper-Catalyzed Synthesis of Pyrrolo[1,2-c]quinazolines and Pyrrolo[2,1-a]isoquinolines and Antiplasmodial Evaluation. Journal of Organic Chemistry, v. 88, n. 13, p. 10-pg., 2023-06-05. (16/20609-8, 13/07600-3, 14/50249-8, 17/19940-4, 20/12904-5, 20/10349-4, 22/01066-4)