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Drug discovery against human infectious diseases

Grant number: 15/26722-8
Support type:Research Projects - Thematic Grants
Duration: March 01, 2017 - February 28, 2022
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Carsten Wrenger
Grantee:Carsten Wrenger
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Co-Principal Investigators:Alessandro Silva Nascimento
Assoc. researchers:Cláudio Romero Farias Marinho ; Helio Alexandre Stefani ; Igor Polikarpov
Associated grant(s):19/00899-0 - Structural dissection of nanoparticle-assisted drug delivery in human infectious diseases, AP.R SPRINT
17/07253-2 - EMU 2015/26722-8 DLS Zetasizer microV, AP.EMU
17/03042-7 - EMU 2015/26722-8 CLARIOstar microplate reader, AP.EMU
17/03047-9 - EMU 2015/26722-8 AVANTI J-30 I Biosafe centrifuge including rotor, AP.EMU
17/04782-4 - EMU 2015/26722-8 AKTA pure gel filtration system, AP.EMU
Associated scholarship(s):19/20219-3 - Structural studies of enzymes involved in vitamin B1 and B6 synthesis in Plasmodium, BP.PD
18/21213-6 - Structural characterization of vitamin B1 and B6 synthesis pathway enzymes in Plasmodium falciparum and Mycobacterium tuberculosis, BP.DD
18/10150-3 - Understanding the cross-talk between SUMOylation and oxidative stress in Plasmodium falciparum, BP.IC
+ associated scholarships 18/08820-0 - Nanoparticle-assisted drug delivery of Vitamin B6 pathway inhibitors in malaria, BP.DR
17/26358-0 - Dissection of the lipoic acid metabolism as druggable target in Malaria, BP.DR
18/00562-2 - Exploitation of vitamin B1 as pro-drug in Malaria and MRSA, BP.IC
17/24901-8 - Structural studies for drug discovery against human infectious diseases, BP.DD - associated scholarships

Abstract

Infectious diseases are a threat to mankind and currently the causative pathogens are spreading geographically due to globalisation and developing drug resistance. Current resistance to chemotherapeutics is occurring to almost all pathogens and therefore new drug targets and/or novel modi of drug target efficacy is urgently needed. In this grant application the focus will be drawn on suicide drug discovery by exploiting the vitamin B1/B6 biosynthetic pathways of the human pathogens Plasmodium falciparum, the parasite responsible for predominate cases of severe malaria, and the multi-resistant bacteria Staphylococcus aureus MRSA. Compounds will be identified and designed for incorporation into pathogens' metabolism after crystal structure evaluation of the respective vitamin B1/B6 biosynthetic enzymes. Thereby the new compounds are intended to poison the respective vitamin-dependent enzyme. Counter selection will be performed against human cells as well as transgenically modified human cells which are expressing nuclear receptors for xenobiotic sensing as reporter gene chimeras. (AU)

Scientific publications (14)
(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)
BATISTA, FERNANDO A.; GYAU, BENJAMIN; VILACHA, JULIANA F.; BOSCH, SORAYA S.; LUNEV, SERGEY; WRENGER, CARSTEN; GROVES, MATTHEW R. New directions in antimalarial target validation. EXPERT OPINION ON DRUG DISCOVERY, v. 15, n. 2, p. 189-202, FEB 1 2020. Web of Science Citations: 0.
LINZKE, MARLEEN; YAN, SUN LIU REI; TARNOK, ATTILA; ULRICH, HENNING; GROVES, MATTHEW R.; WRENGER, CARSTEN. Live and Let Dye: Visualizing the Cellular Compartments of the Malaria Parasite Plasmodium falciparum. Cytometry Part A, NOV 2019. Web of Science Citations: 0.
GAO, KAI; WANG, WENJIA; KRONENBERGER, THALES; WRENGER, CARSTEN; GROVES, MATTHEW R. The Crystal Structure of the Plasmodium falciparum PdxK Provides an Experimental Model for Pro-Drug Activation. CRYSTALS, v. 9, n. 10 OCT 2019. Web of Science Citations: 0.
DE AZEVEDO, ERIKA CHANG; NASCIMENTO, ALESSANDRO S. Energy landscape of the domain movement in Staphylococcus aureus UDP-N-acetylglucosamine 2-epimerase. Journal of Structural Biology, v. 207, n. 2, p. 158-168, AUG 1 2019. Web of Science Citations: 0.
SARTORI, GERALDO RODRIGUES; NASCIMENTO, ALESSANDRO S. Comparative Analysis of Electrostatic Models for Ligand Docking. FRONTIERS IN MOLECULAR BIOSCIENCES, v. 6, JUL 3 2019. Web of Science Citations: 0.
BATISTA, FERNANDO A.; BOSCH, SORAYA S.; BUTZLOFF, SABINE; LUNEV, SERGEY; MEISSNER, KAMILA A.; LINZKE, MARLEEN; ROMERO, ATILIO R.; WANG, CHAO; MUELLER, INGRID B.; DOMLING, ALEXANDER S. S.; GROVES, MATTHEW R.; WRENGER, CARSTEN. Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum. MICROBIOLOGYOPEN, v. 8, n. 7 JUL 2019. Web of Science Citations: 1.
MINARI, KARINE; DE AZEVEDO, ERIKA CHANG; RODRIGUES KIRALY, VANESSA THOMAZ; HELENO BATISTA, FERNANDA APARECIDA; DE MORAES, FABIO ROGERIO; DE MELO, FERNANDO ALVES; NASCIMENTO, ALESSANDRO SILVA; GAVA, LISANDRA MARQUES; INACIO RAMOS, CARLOS HENRIQUE; BORGES, JULIO CESAR. Thermodynamic analysis of interactions of the Hsp90 with adenosine nucleotides: A comparative perspective. International Journal of Biological Macromolecules, v. 130, p. 125-138, JUN 1 2019. Web of Science Citations: 1.
MEISSNER, KAMILA ANNA; KRONENBERGER, THALES; MALTAROLLO, VINICIUS GONCALVES; GOULART TROSSINI, GUSTAVO HENRIQUE; WRENGER, CARSTEN. Targeting the Plasmodium falciparum plasmepsin V by ligand-based virtual screening. CHEMICAL BIOLOGY & DRUG DESIGN, v. 93, n. 3, p. 300-312, MAR 2019. Web of Science Citations: 2.
SCARPELLI, PEDRO H.; TESSARIN-ALMEIDA, GIULLIANA; VICOSO, KENIA LOPES; LIMA, WANIA REZENDE; BORGES-PEREIRA, LUCAS; MEISSNER, KAMILA ANNA; WRENGER, CARSTEN; RAFAELLO, ANNA; RIZZUTO, ROSARIO; POZZAN, TULLIO; GARCIA, CELIA R. S. Melatonin activates FIS1, DYN1, and DYN2 Plasmodium falciparum related-genes for mitochondria fission: Mitoemerald-GFP as a tool to visualize mitochondria structure. Journal of Pineal Research, v. 66, n. 2 MAR 2019. Web of Science Citations: 4.
VASCONCELOS, STANLEY N. S.; MEISSNER, KAMILA A.; FERRAZ, WITOR R.; TROSSINI, GUSTAVO H. G.; WRENGER, CARSTEN; STEFANI, HELIO A. Indole-3-glyoxyl tyrosine: synthesis and antimalarial activity against Plasmodium falciparum. Future Medicinal Chemistry, v. 11, n. 6, p. 525-538, MAR 2019. Web of Science Citations: 2.
KRUGER, ARNE; ZIMBRES, FLAVIA M.; KRONENBERGER, THALES; WRENGER, CARSTEN. Molecular Modeling Applied to Nucleic Acid-Based Molecule Development. BIOMOLECULES, v. 8, n. 3 SEP 2018. Web of Science Citations: 4.
LUNEV, SERGEY; BUTZLOFF, SABINE; ROMERO, ATILIO R.; LINZKE, MARLEEN; BATISTA, FERNANDO A.; MEISSNER, KAMILA A.; MUELLER, INGRID B.; ADAWY, ALAA; WRENGER, CARSTEN; GROVES, MATTHEW R. Oligomeric interfaces as a tool in drug discovery: Specific interference with activity of malate dehydrogenase of Plasmodium falciparum in vitro. PLoS One, v. 13, n. 4 APR 25 2018. Web of Science Citations: 3.
LUNEV, SERGEY; BOSCH, SORAYA S.; BATISTA, FERNANDO A.; WANG, CHAO; LI, JINGYAO; LINZKE, MARLEEN; KRUITHOF, PAUL; CHAMOUN, GEORGE; DOMLING, ALEXANDER S. S.; WRENGER, CARSTEN; GROVES, MATTHEW R. Identification of a non-competitive inhibitor of Plasmodium falciparum aspartate transcarbamoylase. Biochemical and Biophysical Research Communications, v. 497, n. 3, p. 835-842, MAR 11 2018. Web of Science Citations: 0.
BORGES-PEREIRA, LUCAS; MEISSNER, KAMILA ANNA; WRENGER, CARSTEN; GARCIA, CELIA R. S. Plasmodium falciparum GFP-E-NTPDase expression at the intraerythrocytic stages and its inhibition blocks the development of the human malaria parasite. PURINERGIC SIGNALLING, v. 13, n. 3, p. 267-277, SEP 2017. Web of Science Citations: 2.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.