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Development of lead agents for prophylaxis and treatment of cardiovascular diseases

Grant number: 17/07972-9
Support type:Regular Research Grants
Duration: April 01, 2018 - March 31, 2020
Field of knowledge:Biological Sciences - Biochemistry
Cooperation agreement: University of Nottingham
Principal Investigator:Maria Luiza Vilela Oliva
Grantee:Maria Luiza Vilela Oliva
Principal investigator abroad: Jonas Emsley
Institution abroad: University of Nottingham, University Park, England
Home Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). 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 (5)
(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)
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. Web of Science Citations: 0.
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.; VILELA OLIVA, MARIA LUIZA; EMSLEY, JONAS. 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. Web of Science Citations: 0.
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. Web of Science Citations: 0.
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.; OLIVA, V, MARIA LUIZA. 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. Web of Science Citations: 0.
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. Web of Science Citations: 1.

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