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Drug discovery against human infectious diseases

Grant number: 15/26722-8
Support Opportunities:Research Projects - Thematic Grants
Duration: March 01, 2017 - February 29, 2024
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Carsten Wrenger
Grantee:Carsten Wrenger
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Pesquisadores principais:
Alessandro Silva Nascimento
Associated 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):22/01812-8 - Interference with the Assembly of SARS-CoV-2 virions Targeting E Protein by rational drug design, BP.DR
21/00124-8 - Analysis of the SUMOylation of Plasmodium falciparum proteins during oxidative stress in erythrocytes with glucose-6-phosphate dehydrogenase deficiency, BP.MS
20/12277-0 - Drug discovery against human infectious diseases, BP.PD
 + associated scholarships 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
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)

Articles published in Agência FAPESP Newsletter about the research grant:
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Scientific publications (30)
(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)
LUNEV, SERGEY; BOSCH, SORAYA S.; BATISTA, FERNANDO A.; WANG, CHAO; LI, JINGYAO; LINZKE, MARLEEN; KRUITHOF, PAUL; CHAMOUN, GEORGE; DOMLING, ALEXANDER S. S.; WRENGER, CARSTEN; et al. Identification of a non-competitive inhibitor of Plasmodium falciparum aspartate transcarbamoylase. Biochemical and Biophysical Research Communications, v. 497, n. 3, p. 835-842, . (15/26722-8, 13/17577-9, 14/23330-9)
BOSCH, SORAYA S.; LUNEV, SERGEY; BATISTA, FERNANDO A.; LINZKE, MARLEEN; KRONENBERGER, THALES; DOMLING, ALEXANDER S. S.; GROVES, MATTHEW R.; WRENGER, CARSTEN. Molecular Target Validation of Aspartate Transcarbamoylase from Plasmodium falciparum by Torin 2. ACS INFECTIOUS DISEASES, v. 6, n. 5, p. 986-999, . (17/03966-4, 15/26722-8, 13/17577-9, 14/23330-9)
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, . (17/03966-4, 15/26722-8, 13/17577-9)
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, . (12/12807-3, 14/23330-9, 13/10288-1, 16/24790-9, 15/26722-8)
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, . (15/13684-0, 17/18173-0, 15/26722-8)
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, . (13/17960-7, 12/12807-3, 15/26722-8, 12/00424-2, 17/25543-8, 16/24790-9)
SARTORI, GERALDO RODRIGUES; NASCIMENTO, ALESSANDRO S.. Comparative Analysis of Electrostatic Models for Ligand Docking. FRONTIERS IN MOLECULAR BIOSCIENCES, v. 6, . (15/13684-0, 17/18173-0, 15/26722-8)
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.; et al. Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum. MICROBIOLOGYOPEN, v. 8, n. 7, . (17/03966-4, 15/26722-8, 16/24790-9, 14/23330-9, 13/17577-9)
PILLAT, MICHELI MAINARDI; KRUGER, ARNE; FERREIRA GUIMARAES, LARA MENDES; LAMEU, CLAUDIANA; DE SOUZA, EDMARCIA ELISA; WRENGER, CARSTEN; ULRICH, HENNING. Insights in Chloroquine Action: Perspectives and Implications in Malaria andCOVID-19. Cytometry Part A, v. 97, n. 9, . (18/07366-4, 18/08820-0, 15/26722-8, 15/19128-2)
SUMAM DE OLIVEIRA, DAFFINY; KRONENBERGER, THALES; PALMISANO, GIUSEPPE; WRENGER, CARSTEN; DE SOUZA, EDMARCIA ELISA. Targeting SUMOylation in Plasmodium as a Potential Target for Malaria Therapy. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, . (18/10150-3, 20/04923-0, 19/26771-0, 20/12277-0, 17/03966-4, 18/18257-1, 18/15549-1, 15/26722-8)
DOMBROWSKI, JAMILLE GREGORIO; BARATEIRO, ANDRE; MACHADO PEIXOTO, ERIKA PAULA; CLAUDIO DA SILVA BARROS, ANDRE BOLER; DE SOUZA, RODRIGO MEDEIROS; CLARK, TAANE GREGORY; CAMPINO, SUSANA; WRENGER, CARSTEN; WUNDERLICH, GERHARD; PALMISANO, GIUSEPPE; et al. Adverse pregnancy outcomes are associated with Plasmodium vivax malaria in a prospective cohort of women from the Brazilian Amazon. PLoS Neglected Tropical Diseases, v. 15, n. 4, . (17/03966-4, 17/03939-7, 18/18257-1, 19/12068-5, 15/26722-8, 17/24267-7, 20/06747-4, 18/20468-0, 20/04923-0, 18/15549-1, 17/05782-8)
PRATA, ISADORA OLIVEIRA; GALINDO CUBILLOS, ELIANA FERNANDA; KRUGER, ARNE; BARBOSA, DEIBS; MARTINS, JOAQUIM; SETUBAL, JOAO CARLOS; WUNDERLICH, GERHARD. Plasmodium falciparum Acetyl-CoA Synthetase Is Essential for Parasite Intraerythrocytic Development and Chromatin Modification. ACS INFECTIOUS DISEASES, v. 7, n. 12, p. 3224-3240, . (17/24267-7, 16/12659-5, 18/08820-0, 15/26722-8)
REI YAN, SUN L.; WAKASUQUI, FELIPE; WRENGER, CARSTEN. Point-of-care tests for malaria: speeding up the diagnostics at the bedside and challenges in malaria cases detection. DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE, v. 98, n. 3, . (15/26722-8, 17/26358-0)
KRUGER, ARNE; DE JESUS SANTOS, ANA PAULA; DE SA, VANESSA; ULRICH, HENNING; WRENGER, CARSTEN. Aptamer Applications in Emerging Viral Diseases. PHARMACEUTICALS, v. 14, n. 7, . (18/07366-4, 15/26722-8, 17/03966-4, 15/26642-4)
LAZARI, LUCAS CARDOSO; GHILARDI, FABIO DE ROSE; ROSA-FERNANDES, LIVIA; ASSIS, DIEGO M.; NICOLAU, JOSE CARLOS; SANTIAGO, VERONICA FEIJOLI; DALCOQUIO, TALIA FALCAO; ANGELI, CLAUDIA B.; BERTOLIN, ADRIADNE JUSTI; MARINHO, CLAUDIO R. F.; et al. Prognostic accuracy of MALDI-TOF mass spectrometric analysis of plasma in COVID-19. LIFE SCIENCE ALLIANCE, v. 4, n. 8, . (20/04705-2, 18/15549-1, 17/03966-4, 15/26722-8, 18/20468-0, 20/04923-0, 18/18257-1)
BARRA, ANGELICA LUANA C.; ULLAH, NAJEEB; MORAO, LUANA G.; WRENGER, CARSTEN; BETZEL, CHRISTIAN; NASCIMENTO, ALESSANDRO S.. Structural Dynamics and Perspectives of Vitamin B6 Biosynthesis Enzymes in Plasmodium: Advances and Open Questions. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, . (18/21213-6, 19/20219-3, 20/03983-9, 15/13684-0, 19/26428-3, 15/26722-8, 17/03966-4)
COUTINHO, JOAO V. P.; ROSA-FERNANDES, LIVIA; MULE, SIMON NGAO; DE OLIVEIRA, GILBERTO SANTOS; MANCHOLA, NUBIA CAROLINA; SANTIAGO, VERONICA FEIJOLI; COLLI, WALTER; WRENGER, CARSTEN; MANSO ALVES, MARIA JULIA; PALMISANO, GIUSEPPE. The thermal proteome stability profile of Trypanosoma cruzi in epimastigote and trypomastigote life stages. JOURNAL OF PROTEOMICS, v. 248, . (18/13283-4, 18/15549-1, 14/06863-3, 17/03966-4, 15/26722-8, 17/19854-0, 17/04032-5, 18/18257-1)
DE PAULA, KARINA; SANTOS, JADEMILSON C.; MAFUD, ANA CAROLINA; NASCIMENTO, ALESSANDRO S.. Tetrazoles as PPAR gamma ligands: A structural and computational investigation. JOURNAL OF MOLECULAR GRAPHICS & MODELLING, v. 106, . (10/15376-8, 20/03983-9, 14/06565-2, 15/26722-8)
BARRA, ANGELICA LUANA C.; DANTAS, LIVIA DE OLIVEIRA C.; MORAO, LUANA GALVAO; GUTIERREZ, RAISSA F.; POLIKARPOV, IGOR; WRENGER, CARSTEN; NASCIMENTO, ALESSANDRO S.. Essential Metabolic Routes as a Way to ESKAPE From Antibiotic Resistance. FRONTIERS IN PUBLIC HEALTH, v. 8, . (15/13684-0, 17/18173-0, 15/26722-8)
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, v. 97, n. 7, SI, . (12/50880-4, 17/03966-4, 15/26722-8, 14/23330-9, 17/26358-0, 12/50393-6)
KRUGER, ARNE; ZIMBRES, FLAVIA M.; KRONENBERGER, THALES; WRENGER, CARSTEN. Molecular Modeling Applied to Nucleic Acid-Based Molecule Development. BIOMOLECULES, v. 8, n. 3, . (17/03966-4, 18/08820-0, 15/26722-8)
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, . (14/03644-9, 16/24790-9, 17/03966-4, 15/26722-8)
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; et al. 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, . (12/12807-3, 11/51295-5, 14/14347-5, 15/26722-8)
GOMES, LAURA CORDEIRO; SANSON, MARINA CORDEIRO GOMES; BRAININ, PHILIP; DE MELO, MARIA DA CONCEICAO VIEIRA; DE SOUZA, RODRIGO MEDEIROS; MAZARO, JANAINA; LIMA, KARINE OLIVEIRA; RESENDE, JUNIA SILVA; VIEIRA, ISABELLE VICTORIA MARTINS; MESQUITA, EDINILSON DA SILVA; et al. Levels of hepatitis B antibody titers are affected by age and doses gap time in children from a high endemic area of the western Amazon. PLoS One, v. 16, n. 7, . (18/20468-0, 18/18257-1, 18/15549-1, 15/26722-8, 14/06863-3)
SOUZA JUNIOR, DOUGLAS RICARDO; MARTINS SILVA, AMANDA RIBEIRO; ROSA-FERNANDES, LIVIA; REIS, LORENNA ROCHA; ALEXANDRIA, GABRIELLY; BHOSALE, SANTOSH D.; GHILARDI, FABIO DE ROSE; DALCOQUIO, TALIA FALCAO; BERTOLIN, ADRIADNE JUSTI; NICOLAU, JOSE CARLOS; et al. HDL proteome remodeling associates with COVID-19 severity. JOURNAL OF CLINICAL LIPIDOLOGY, v. 15, n. 6, p. 796-804, . (15/26722-8, 16/00696-3, 20/04923-0, 19/25702-4, 17/07725-1, 18/15549-1, 18/18257-1, 13/07937-8)
LAZARI, LUCAS C.; ZERBINATI, RODRIGO M.; ROSA-FERNANDES, LIVIA; SANTIAGO, VERONICA FEIJOLI; ROSA, KLAISE F.; ANGELI, CLAUDIA B.; SCHWAB, GABRIELA; PALMIERI, MICHELLE; SARMENTO, DMITY J. S.; MARINHO, CLAUDIO R. F.; et al. ALDI-TOF mass spectrometry of saliva samples as a prognostic tool for COVID-1. OURNAL OF ORAL MICROBIOLOG, v. 14, n. 1, . (18/15549-1, 20/06409-1, 20/04923-0, 18/18257-1, 15/26722-8, 17/03966-4, 21/07490-0, 18/20468-0)
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, . (17/03966-4, 14/03644-9, 15/26722-8)
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, . (15/26722-8, 13/25646-0, 17/18173-0, 11/23110-0, 14/07206-6, 12/50161-8, 09/53989-4, 17/07335-9)
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, . (12/12807-3, 10/51593-3, 15/26722-8, 13/10288-1, 11/51295-5)
BRIGANTI, LORENZO; CAPETTI, CAIO; PELLEGRINI, VANESSA O. A.; GHIO, SILVINA; CAMPOS, ELEONORA; NASCIMENTO, ALESSANDRO S.; POLIKARPOV, IGOR. Structural and molecular dynamics investigations of ligand stabilization via secondary binding site interactions in Paenibacillus xylanivorans GH11 xylanase. COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL, v. 19, p. 1557-1566, . (20/03983-9, 15/26722-8, 15/13684-0)

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