Development of lead agents for prophylaxis and treatment of cardiovascular diseases

• Grant number: 17/07972-9
• Support Opportunities: Regular Research Grants
• Start date: April 01, 2018
• End date: March 31, 2021
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Agreement: University of Nottingham
• Principal Investigator: Maria Luiza Vilela Oliva
• Grantee: Maria Luiza Vilela Oliva
• Principal researcher abroad: Jonas Emsley
• Institution abroad: University of Nottingham, University Park, England
• Host Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Cardiovascular disease is a diverse family of diseases encompassing heart attacks and strokes which collectively account for the single major cause of morbidity worldwide with an urgent need for new medicines. As an example, Ischemic stroke is a devastating disease that represents the primary reason for sustained disability and the second leading cause of death worldwide. The holy grail of anticoagulant therapy is to control thrombosis without compromising haemostasis termed "safer anticoagulation" and delivery of a new class of medicines in this area is the main goal of our research. The activity of coagulation Factor XII (FXII), unlike all other coagulation proteases, is not implicated in the maintenance of haemostasis, whereas FXII deficiency protects from thrombosis. Anticoagulants used for ischaemic stroke and venous thromboembolism are associated with bleeding risks. Formation of FXIIa initiates the contact activation pathway and there is evidence that FXIIa is dispensable for haemostasis, whereas blocking of FXIIa activity is sufficient to suppress thrombosis. In addition, the FXIIa enzyme drives bradykinin generation which is linked to attacks of swelling in patients with hereditary angioedema. Peter Fischer, Jonas Emsley, Lodewijk Dekker group (Nottingham) are the first to identify small-molecule selective FXIIa inhibitors and to determine the first crystal structure of the FXII protease and we now propose to combine this research expertise with the group of Maria Luiza Vilela Oliva (UNIFESP-Brazil) who has expertise in assays of the contact system and animal models of cardiovascular disease and studying natural product inhibitors of the contact system. The immediate goal for this grant is a medium impact and a high impact publication combining data from the groups at Nottingham and Brazil and completing two long term studies into inhibitors of FXIIa drawing together protein structural data with FXIIa inhibitor in vitro and in vivo data. (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)

LOBO, YARA A.; BONAZZA, CAMILA; BATISTA, FABRICIO P.; CASTRO, RODRIGO A.; BONTURI, CAMILA R.; SALU, BRUNO R.; SINIGAGLIA, RITA DE CASSIA; TOMA, LENY; VICENTE, CAROLINA M.; PIDDE, GISELLE; et al. EcTI impairs survival and proliferation pathways in triple-negative breast cancer by modulating cell-glycosaminoglycans and inflammatory cytokines. Cancer Letters, v. 491, p. 108-120, OCT 28 2020. (17/06630-7, 17/07972-9)

PATHAK, MONIKA; MANNA, ROSA; LI, CHAN; KAIRA, BUBACARR G.; HAMAD, BADRALDIN KAREEM; BELVISO, BENNY DANILO; BONTURI, CAMILA R.; DREVENY, INGRID; FISCHER, PETER M.; DEKKER, LODEWIJK V.; et al. Crystal structures of the recombinant -factor XIIa protease with bound Thr-Arg and Pro-Arg substrate mimetics. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, v. 75, p. 14-pg., 2019-06-01. (17/06630-7, 17/07972-9)

BONTURI, CAMILA RAMALHO; CABRAL SILVA, MARIANA CRISTINA; MOTALN, HELENA; SALU, BRUNO RAMOS; FERREIRA, RODRIGO DA SILVA; BATISTA, FABRICIO PEREIRA; DOS SANTOS CORREIA, MARIA TEREZA; GUEDES PAIVA, PATRICIA MARIA; TURNSEK, TAMARA LAH; VILELA OLIVA, MARIA LUIZA. A Bifunctional Molecule with Lectin and Protease Inhibitor Activities Isolated from Crataeva tapia Bark Significantly Affects Cocultures of Mesenchymal Stem Cells and Glioblastoma Cells. Molecules, v. 24, n. 11, JUN 1 2019. (17/07972-9, 17/06630-7)

FERREIRA, R. S.; BRITO, V, M.; NAPOLEAO, T. H.; SILVA, M. C. C.; PAIVA, P. M. G.; OLIVA, V, M. L.. Effects of two protease inhibitors from Bauhinia bauhinoides with different specificity towards gut enzymes of Nasutitermes corniger and its survival. Chemosphere, v. 222, p. 364-370, MAY 2019. (17/07972-9, 17/06630-7)

YOO IM, SONIA; RAMALHO BONTURI, CAMILA; MITI NAKAHATA, ADRIANA; RYUICHI NAKAIE, CLOVIS; POTT, ARNILDO; POTT, VALI JOANA; VILELA OLIVA, MARIA LUIZA. Differences in the Inhibitory Specificity Distinguish the Efficacy of Plant Protease Inhibitors on Mouse Fibrosarcoma. PLANTS-BASEL, v. 10, n. 3, MAR 2021. (17/07972-9, 17/06630-7, 19/22243-9)

NUNES, NATALIA N. S.; FERREIRA, RODRIGO S.; DE SA, LEONARDO F. R.; DE OLIVEIRA, ANTONIA ELENIR A.; OLIVA, V, MARIA LUIZA. A novel cysteine proteinase inhibitor from seeds of Enterolobium contortisiliquum and its effect on Callosobruchus maculatus larvae. BIOCHEMISTRY AND BIOPHYSICS REPORTS, v. 25, MAR 2021. (17/07972-9, 17/06630-7)

PATHAK, MONIKA; MANNA, ROSA; LI, CHAN; KAIRA, BUBACARR G.; HAMAD, BADRALDIN KAREEM; BELVISO, BENNY DANILO; BONTURI, CAMILA R.; DREVENY, INGRID; FISCHER, PETER M.; DEKKER, LODEWIJK V.; et al. Crystal structures of the recombinant -factor XIIa protease with bound Thr-Arg and Pro-Arg substrate mimetics. ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, v. 75, n. 6, p. 578-591, JUN 2019. (17/07972-9, 17/06630-7)

DUTRA DAS MERCES, AURENICE ARRUDA; FERREIRA, RODRIGO DA SILVA; SANTOS SILVA, KARCIANO JOSE; SALU, BRUNO RAMOS; MACIEL, JACKELINE DA COSTA; OLIVEIRA AGUIAR, JOSE ALBINO; TASHIMA, ALEXANDRE KEIJI; VILELA OLIVA, MARIA LUIZA; DE CARVALHO JUNIOR, LUIZ BEZERRA. Identification of blood plasma proteins using heparin-coated magnetic chitosan particles. Carbohydrate Polymers, v. 247, NOV 1 2020. (17/06630-7, 17/07972-9)

OLIVEIRA, CLEIDE; VALOIS, MAYARA VIOTO; OTTAIANO, TATIANA FONTES; MIRANDA, ANTONIO; HANSEN, DAIANE; SAMPAIO, MISAKO UEMURA; VILELA OLIVA, MARIA LUIZA; DE ABREU MAFFEI, FRANCISCO HUMBERTO. The recombinant plant Bauhinia bauhinioides elastase inhibitor reduces rat thrombus without alterations in hemostatic parameters. SCIENTIFIC REPORTS, v. 11, n. 1, JUN 29 2021. (17/07972-9, 17/06630-7)

SALU, BRUNO R.; PANDO, SILVANA CRISTINA; DE BRITO, V, MARLON; MEDINA, ANDRE FERNANDO; ODEI-ADDO, FRANK; FROST, CARMINITA; NAUDE, RYNO; SAMPAIO, MISAKO U.; EMSLEY, JONAS; MAFFEI, FRANCISCO HUMBERTO A.; et al. Improving the understanding of plasma kallikrein contribution to arterial thrombus formation using two plant protease inhibitors. PLATELETS, v. 30, n. 3, p. 305-313, APR 3 2019. (17/06630-7, 17/07972-9)

SALLAI, ROBERTO CARLOS; SALU, BRUNO RAMOS; SILVA-LUCCA, ROSEMEIRE APARECIDA; ALVES, FLIVIO LOPES; NAPOLEAO, THIAGO HENRIQUE; GUEDES PAIVA, PATRICIA MARIA; FERREIRA, RODRIGO DA SILVA; SAMPAIO, MISAKO UEMURA; VILELA OLIVA, MARIA LUIZA. Biotechnological Potential of Araucaria angustifolia Pine Nuts Extract and the Cysteine Protease Inhibitor AaCI-2S. PLANTS-BASEL, v. 9, n. 12, DEC 2020. (17/07972-9, 17/06630-7)

FERREIRA, RODRIGO DA SILVA; NAPOLEAO, THIAGO HENRIQUE; SILVA-LUCCA, ROSEMEIRE A.; CABRAL SILVA, MARIANA CRISTINA; GUEDES PAIVA, PATRICIA MARIA; VILELA OLIVA, MARIA LUIZA. The effects of Enterolobium contortisiliquum serine protease inhibitor on the survival of the termite Nasutitermes corniger, and its use as affinity adsorbent to purify termite proteases. Pest Management Science, v. 75, n. 3, p. 632-638, MAR 2019. (17/07972-9, 17/06630-7)

VALOIS, MAYARA VIOTO; DE OLIVEIRA, CLEIDE; LAPA, ANTONIO JOSE; SOUCCAR, CADEN; VILELA OLIVA, MARIA LUIZA. Bauhinia Protease Inhibitors Attenuate Gastric Ulcer by Blocking Neutrophil Enzymes. Planta Medica, v. 87, n. 01/02, p. 169-176, FEB 2021. (17/07972-9)

OLIVA, MARIA LUIZA VILELA; DREVENY, INGRID; EMSLEY, JONAS. Exosites expedite blood coagulation. Journal of Biological Chemistry, v. 295, n. 45, p. 2-pg., 2020-11-06. (19/22243-9, 17/06630-7, 17/07972-9)