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Effects of peptides related to the structures of the inhibitors isolated from Enterolobium contortisiliquum, EcTI, and of the recombinant chimeric inhibitor of Bauhinia bauhinioides, rBbKIm, in model of Melanoma

Grant number: 18/21372-7
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): December 01, 2018
Effective date (End): March 31, 2022
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal Investigator:Maria Luiza Vilela Oliva
Grantee:Kathleen Chwen Ming Lie
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:17/06630-7 - 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, AP.TEM

Abstract

Melanoma, malignant skin Cancer developed in melanocytes, has been shown important for researches due to his high degree of metastasis and low chances of cure once diagnosed late. According to INCA, the estimate of new cases for non-Melanoma Skin Cancer by 2018 will be 85,170 for men and 80,410 for women and for Melanoma Skin Cancer, 2,920 for men and 3,340 for women. In tumors, proteolysis is facilitated by proteases of tumor cells that are secreted or bound to their surface. Overexpression or activation of a protease provides a proteolytically active environment surrounding the tumor. Inhibitors of these activities, especially the protease inhibitors found in legumes, are potential candidates for the control of these events by blocking the progression of Cancer. Inhibitors present in legumes characterized by Profa. Maria Luiza Oliva present atypical features both in structural and functional aspects and are being used in models of inflammation, Thrombosis and Cancer. The group also constructed a chimeric form (Sumikawa et al., 2010) called rBbKIm (Bauhinia bauhinoides Kallikrein inhibitor modified) whose base structure is that of the inhibitor present in B. bauhinoides but modified so as to contain the EPVARGDG sequences (position 21-28 ) and GERD (position 127-130) of BrTI (characterized inhibitor of B. rufa by Nakahata et al., 2006). The deleterious effect of this protein on prostate Cancer DU145 and PC3 lines was observed by Ferreira et al., 2014. Studies already initiated show that rBbKIm is capable of inhibiting the tissue kallikreins KLK 6 and 7, serine protease with important developmental role of Melanoma (Thierauf et al., 2017; Delaunay et al., 2017). Yet another inhibitor, Enterolobium contortisiliquum trypsin inhibitor (EcTI), is already being investigated for Melanoma, and the results are quite promising, both in relation to the use of the protein and in synthetic peptide fragments structurally related to the protein. Thus, this project proposes to extend the studies using the two protease inhibitors alone or in combination treatment, in addition to using fragments of the inhibitor structures on human Melanoma cells SK-MEL-28 in vitro in an attempt to establish the mechanisms involved and the relationship between the structure and the kinetic parameters of inhibition relative to the target proteases. (AU)