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Evaluation of modulators of the activity of proteases involved in pathological processes

Abstract

Proteases are involved in many physiological processes attending to the metabolic and functional demand of the organisms to which they participate. However, in many situations these same proteases can trigger unwanted processes that establish pathologies in humans. Therefore, the modulation of its activities is a way of controlling its actions in pathogenic mechanisms such as tumor progression, metastasis, viral capsid processing, bacterial toxin processing, in facilitating the invasion of parasitic microorganisms and fungi. Among these proteases we have the cysteine proteases lysosomal cathepsins L and B. Cathepsins, in addition to their role in metastatic processes, are also responsible for an important role in the execution of the apoptotic program in several types of tumoral strains, since this enzyme needs to be transferred from the lysosome to the cytosol, where it degrades proteins involved in apoptosis. Cathepsins are involved in programmed cell death and senescence, and in the control of cell proliferation and differentiation. By their deleterious actions in the human organism, these proteases become interesting targets for the development of new drugs. In this context, our objective is to evaluate two families of molecules, one belonging to the alkyltriazoles and alkylphospholipids (21 molecules) and another belonging to the organometallic palladium complexes (8 molecules). In order to do so, we will carry out a screening of inhibitory activity, determination of inhibitory potential IC50, determination of inhibition mechanism and constant of dissociation of inhibitor Ki, determination of the microscopic constants belonging to Ki = k -3 / k3 by time course kinetics, molecular docking having the kinetic data as beacon parameters for modeling. We will evaluate the cytotoxicity of the compounds on leukemic cell lines using flow cytometry and determining the type of cell death. (AU)

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Scientific publications (9)
(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)
DE MOURA, THALES REGGIANI; ZANETTI, RENAN DIEGO; SILVA, DEBORA EDUARDA SOARES; DE FARIAS, RENAN LIRA; MAURO, ANTONIO EDUARDO; PEREIRA, JOSE CLAYSTON MELO; DE SOUZA, ALINE APARECIDA; DA SILVA SIQUEIRA, FABIO; DE SOUZA JUDICE, WAGNER ALVES; LIMA, MAURO ALMEIDA; ROCHA, FILLIPE VIEIRA; DEFLON, VICTOR MARCELO; VIEIRA DE GODOY NETTO, ADELINO. Palladium(ii) complexes bearing 1-iminothiolate-3,5-dimethylpyrazoles: synthesis, cytotoxicity, DNA binding and enzymatic inhibition studies. NEW JOURNAL OF CHEMISTRY, v. 44, n. 45, p. 19891-19901, DEC 7 2020. Web of Science Citations: 0.
KAUFFMANN, ANGELICA C.; OLIVEIRA, RHAYSSA G. S. P.; DOURADO, THAINARA A.; SOARES, IURI N.; DE SOUSA, PAULO T.; RIBEIRO, TEREZA A. N.; JACINTO, MARCOS J.; DE SOUZA, GABRIEL L. C.; JUDICE, WAGNER A. DE S.; EMILIANO, MARLI DE F. C.; VIANNA, LUAN DOS S.; DE CARVALHO, MARIO G.; SILVA, VIRGINIA C. P. Eleocarpanthraquinone, a novel anthraquinone from Rhamnidium elaeocarpum (Rhamnaceae). Tetrahedron Letters, v. 61, n. 45 NOV 5 2020. Web of Science Citations: 0.
COSTA, CLAUDIA A.; LOPES, RAYSSA M.; FERRAZ, LETICIA S.; ESTEVES, GABRIELA N. N.; DI IORIO, JULIANA F.; SOUZA, ALINE A.; DE OLIVEIRA, ISADORA M.; MANARIN, FLAVIA; JUDICE, WAGNER A. S.; STEFANI, HELIO A.; RODRIGUES, TIAGO. Cytotoxicity of 4-substituted quinoline derivatives: Anticancer and antileishmanial potential. Bioorganic & Medicinal Chemistry, v. 28, n. 11 JUN 1 2020. Web of Science Citations: 0.
DA CUNHA, GISLAINE A.; DE SOUZA, RONAN F. F.; DE FARIAS, RENAN L.; MOREIRA, MARIETE B.; SILVA, DEBORA E. S.; ZANETTI, RENAN D.; GARCIA, DANIEL M.; SPINDOLA, DANIEL G.; MICHELIN, LUIS F. G.; BINCOLETTO, CLAUDIA; DE SOUZA, ALINE A.; ANTUNES, ALYNE A.; JUDICE, WAGNER A. DE S.; LEITAO, RENAN C. F.; DEFLON, VICTOR M.; MAURO, ANTONIO E.; NETTO, ADELINO V. G. Cyclopalladated compounds containing 2,6-lutidine: Synthesis, spectral and biological studies. Journal of Inorganic Biochemistry, v. 203, FEB 2020. Web of Science Citations: 4.
VITAL, WAGNER D.; TORQUATO, HERON F. V.; PASSOS JESUS, LARISSA DE OLIVEIRA; DE SOUZA JUDICE, WAGNER ALVES; DA SILVA, MARIA FATIMA DAS G. F.; RODRIGUES, TIAGO; JUSTO, GISELLE ZENKER; VEIGA, THIAGO A. M.; PAREDES-GAMERO, EDGAR J. 4-Deoxyraputindole C induces cell death and cell cycle arrest in tumor cell lines. Journal of Cellular Biochemistry, v. 120, n. 6, p. 9608-9623, JUN 2019. Web of Science Citations: 1.
DE NOVAIS, LEICE M. R.; DE ARUEIRA, CAUANE C. O.; FERREIRA, LUIZ F.; RIBEIRO, TEREZA A. N.; SOUSA, JR., PAULO T.; JACINTO, MARCOS J.; DE CARVALHO, MARIO G.; JUDICE, WAGNER A. S.; JESUS, LARISSA O. P.; DE SOUZA, ALINE A.; TORQUATO, HERON F. V.; PAREDES-GAMERO, EDGAR J.; SILVA, VIRGINIA C. 4 `-Hydroxy-6,7-methylenedioxy-3-methoxyflavone: A novel flavonoid from Dulacia egleri with potential inhibitory activity against cathepsins B and L. Fitoterapia, v. 132, p. 26-29, JAN 2019. Web of Science Citations: 1.
ANTUNES, ALYNE ALEXANDRINO; PASSOS JESUS, LARISSA DE OLIVEIRA; MANFREDI, MARCELLA ARAUJO; DE SOUZA, ALINE APARECIDA; MARCONDES MACHADO, MAURICIO FERREIRA; MORAES E SILVA, PAMELA; ICIMOTO, MARCELO YUDI; JULIANO, MARIA APARECIDA; JULIANO, LUIZ; DE SOUZA JUDICE, WAGNER ALVES. Thermodynamic analysis of Kex2 activity: The acylation and deacylation steps are potassium- and substrate-dependent. Biophysical Chemistry, v. 235, p. 29-39, APR 2018. Web of Science Citations: 1.
COELHO, CAMILA M.; DOS SANTOS, THIAGO; FREITAS, POLIANY G.; NUNES, JULIANA B.; MARQUES, MARCOS J.; PADOVANI, CAMILA G. D.; JUDICE, WAGNER A. S.; CAMPS, IHOSVANY; DA SILVEIRA, NELSON J. F.; CARVALHO, DIOGO T.; VELOSO, MARCIA P. Design, Synthesis, Biological Evaluation and Molecular Modeling Studies of Novel Eugenol Esters as Leishmanicidal Agents. Journal of the Brazilian Chemical Society, v. 29, n. 4, p. 715-728, APR 2018. Web of Science Citations: 2.
CAMILA M. COELHO; THIAGO DOS SANTOS; POLIANY G. FREITAS; JULIANA B. NUNES; MARCOS J. MARQUES; CAMILA G. D. PADOVANI; WAGNER A. S. JÚDICE; IHOSVANY CAMPS; NELSON J. F. DA SILVEIRA; DIOGO T. CARVALHO; MARCIA P. VELOSO. Design, Synthesis, Biological Evaluation and Molecular Modeling Studies of Novel Eugenol Esters as Leishmanicidal Agents. Journal of the Brazilian Chemical Society, v. 29, n. 4, p. -, Abr. 2018.

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