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Fragments derived from the structure of protease inhibitors with selectivity for inhibition of mammalian and microorganism enzymes and its role as an anti-inflammatory, antimicrobial, antithrombotic and anti- tumor agent: mechanism of action

Grant number: 17/06630-7
Support Opportunities:Research Projects - Thematic Grants
Duration: March 01, 2018 - May 31, 2024
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal Investigator:Maria Luiza Vilela Oliva
Grantee:Maria Luiza Vilela Oliva
Host Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Pesquisadores principais:
Francisco Humberto de Abreu Maffei
Associated researchers: Alexander Wlodawer ; Alexandre Keiji Tashima ; Alioscka Augusto Sousa ; Clovis Ryuichi Nakaie ; Débora Conte Kimura Lichtenecker ; Edgar Julian Paredes-Gamero ; Edna Aparecida Leick ; Helena Motaln ; Ingrid Dreveny ; Iolanda de Fátima Lopes Calvo Tibério ; Jacek Lubkowski ; Joana Tomomi Sumikawa ; Jonas Emsley ; José Carlos Costa Baptista-Silva ; Jose Ronnie Carvalho de Vasconcelos ; Luiz Juliano Neto ; Maria Aparecida Juliano ; Maria Kouyoumdjian ; Maria Tereza dos Santos Correia ; Mariana Cristina Cabral Silva ; Marlon V. de Brito ; Miriam Camargo Guarnieri Ogata ; Misako Uemura Sampaio ; Patrícia Maria Guedes Paiva ; Renato Fraga Righetti ; Roberto Carlos Sallai ; Rodrigo Barbosa de Aguiar ; Rosemeire Aparecida da Silva de Lucca ; Sang Won Han ; Sheila Siqueira Andrade ; Sonia Aparecida de Andrade Chudzinski ; Tatiana Fontes Ottaiano ; Thaysa Paschoalin
Associated grant(s):19/23670-8 - Multi-User Equipment approved in the grant 2017/06630-7: lyophilizer, AP.EMU
Associated scholarship(s):22/10383-3 - Expression, purification of Bauhinia bauhinioides Cruzipain Inhibitor (BbCI) an investigation of action on triple-negative breast cancer cellular events, BP.MS
21/13061-4 - Evaluation of EcTI protease inhibitor and it derived peptide associated with Paclitaxel and Doxorubicin in triple-negative breast Cancer cells, BP.IC
21/13063-7 - Action of peptides derived from the natural protein EcTI combined with Temozolomide in glioblastoma cells, BP.IC
+ associated scholarships 20/00360-0 - Evaluation of CrataBL efficacy for reversal of heparinization, BP.IC
20/01512-9 - Mechanism of action of Enterolobium contortisiliquum-derived mimetic peptides on platelet signaling and function, BP.DD
19/22243-9 - Fragments derived from the structure of protease inhibitors with selectivity for inhibition of mammalian and microorganism enzymes and its role as an anti-inflammatory, antimicrobial, antithrombotic and anti- tumor agent: mechanism of action, BP.PD
18/25282-2 - Analysis of the biological activity of mimetic peptides derived from Enterolobium contortisiliquum seeds on hemostatic parameters and arterial thrombosis, BP.IC
18/21372-7 - Effects of peptides related to the recombinant Bauhinia bauhinioides chimeric inhibitor, rBbKIm, and Crataeva tapia bark lectin, CrataBL, on the Melanoma Cancer model, BP.DD
18/07299-5 - The use of fragments derived from the structure of protease inhibitors isolated from legumes with antithrombotic properties: mechanism of action, BP.PD - associated scholarships

Abstract

Brazilian flora is considered an important source of natural products that may be beneficial to all mankind. Studies of these resources require a concerted effort of the Brazilian scientific institutions. Our research group has been conducting comparative studies of protease inhibitors from leguminous seeds, determining the primary, secondary and tertiary structures, as well as modeling of proteins, in order to identify residues of specific amino acids involved in its interaction with the target protease. Characterization of the interactions between the natural protease inhibitors or technically modified proteases and their targets are being investigated in many biological processes such as inflammation, hemostasis and thrombosis, and tumor development. The research group has extensive experience in kinetic analysis of peptides used as substrates, enzyme inhibitors and agonists. This project proposes to continue the investigation using both proteins and synthetic peptides based on the structures of protease inhibitors and lectins, using models of inflammation, thrombosis and cancer, in vitro and in vivo, in an attempt to establish the involved mechanisms and the relationships between the structure and the kinetic parameters for inhibition of target proteases. Our purpose is to investigate possible therapeutic uses of these substances. The proposed project will provide conditions for continuation of the group's studies involved in the Thematic Project 2009/53766-5, coordinated by Prof. Dr. Maria Luiza V. Oliva, Department of Biochemistry UNIFESP- EPM that over several years have been evaluating the biological significance in the variations of the primary structures of plant proteins in relation to their anti-inflammatory, antimicrobial, antithrombotic and antitumoral properties. (AU)

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Scientific publications (19)
(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)
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, . (17/07972-9, 17/06630-7)
BONTURI, CAMILA RAMALHO; SILVA TEIXEIRA, ANA BEATRIZ; ROCHA, VITORIA MORAIS; VALENTE, PENELOPE FERREIRA; OLIVEIRA, JULIANA RODRIGUES; BEZERRA FILHO, CLOVIS MACEDO; DE FATIMA CORREIA BATISTA, ISABEL; OLIVA, MARIA LUIZA VILELA. Plant Kunitz Inhibitors and Their Interaction with Proteases: Current and Potential Pharmacological Targets. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 9, p. 19-pg., . (17/06630-7, 19/22243-9)
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, . (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, . (17/06630-7, 17/07972-9)
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, . (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, . (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, . (17/06630-7, 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., . (19/22243-9, 17/06630-7, 17/07972-9)
LIE, KATHLEEN CHWEN MING; BONTURI, CAMILA RAMALHO; SALU, BRUNO RAMOS; DE OLIVEIRA, JULIANA RODRIGUES; BONINI GALO, MARCIA; PAIVA, PATRICIA MARIA GUEDES; CORREIA, MARIA TEREZA DOS SANTOS; OLIVA, MARIA LUIZA VILELA. Impairment of SK-MEL-28 Development-A Human Melanoma Cell Line-By the Crataeva tapia Bark Lectin and Its Sequence-Derived Peptides. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 13, p. 27-pg., . (18/21372-7, 17/06630-7)
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, . (17/07972-9, 17/06630-7)
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, . (17/06630-7, 17/07972-9)
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, . (17/07972-9, 17/06630-7)
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, . (17/07972-9, 17/06630-7)
MEDINA, A. F.; SALU, B. R.; DE BRITO, M. V.; BONTURI, C. R.; MENEGHETTI, M. C. Z.; MAFFEI, F. H. A.; OLIVA, M. L. V.. The impairment of plasma kallikrein action on homeostasis by kallikrein inhibitor comprising RGD sequence established a novel target in antithrombotic therapies. Process Biochemistry, v. 122, p. 12-pg., . (17/06630-7)
SANTOS, NATALIA R. M.; DE OLIVEIRA, WESLLEY F.; CABRERA, MARIANA P.; BEZERRA FILHO, CLOVIS M.; PATRIOTA, LEYDIANNE L. S.; NAPOLEA, THIAGO H.; PAIVA, PATRICIA M. G.; OLIVA, MARIA LUIZA V.; CABRAL FILHO, PAULO E.; FONTES, ADRIANA; et al. A fluorescent quantum dot conjugate to probe the interaction of Enterolobium contortisiliquum trypsin inhibitor with cancer cells. International Journal of Biological Macromolecules, v. 252, p. 7-pg., . (17/06630-7)
BONTURI, CAMILA RAMALHO; SALU, BRUNO RAMOS; BONAZZA, CAMILA NIMRI; SINIGAGLIA, RITA DE CASSIA; RODRIGUES, TIAGO; ALVAREZ-FLORES, MIRYAM PAOLA; CHUDZINSKI-TAVASSI, ANA MARISA; OLIVA, MARIA LUIZA VILELA. Proliferation and Invasion of Melanoma Are Suppressed by a Plant Protease Inhibitor, Leading to Downregulation of Survival/Death-Related Proteins. Molecules, v. 27, n. 9, p. 22-pg., . (17/06630-7, 19/22243-9)
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, . (17/07972-9, 17/06630-7, 19/22243-9)
NOGUEIRA, RUBEN SIEDLARCZYK; SALU, BRUNO RAMOS; NARDELLI, VINICIUS GOULART; BONTURI, CAMILA RAMALHO; PEREIRA, MARINA RODRIGUES; MAFFEI, FRANCISCO HUMBERTO DE ABREU; CILLI, EDUARDO MAFFUD; OLIVA, MARIA LUIZA VILELA. A snake venom-analog peptide that inhibits SARS-CoV-2 and papain-like protease displays antithrombotic activity in mice arterial thrombosis model, without interfering with bleeding time. THROMBOSIS JOURNAL, v. 21, n. 1, p. 10-pg., . (17/06630-7, 20/05761-3, 19/22243-9, 20/01512-9)
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., . (17/06630-7, 17/07972-9)

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