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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Semysinthetic biflavonoid Morelloflavone-7,4 `,7 `',3 `'',4 `''-penta-O-butanoyl is a more potent inhibitor of Proprotein Convertases Subtilisin/Kexin PC1/3 than Kex2 and Furin

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Author(s):
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de Souza, Aline Aparecida [1] ; de Andrade, Debora Martins [1] ; Siqueira, Fabio da Silva [1] ; Di Iorio, Juliana Fortes [1] ; Veloso, Marcia Paranho [2] ; Coelho, Camila de Morais [2] ; Junior, Claudio Viegas [3] ; Gontijo, Vanessa Silva [3] ; dos Santos, Marcelo Henrique [4] ; Zorel Meneghetti, Maria Cecilia [5] ; Nader, Helena Bonciani [5] ; dos Santos Tersariol, Ivarne Luis [1, 5] ; Juliano, Luiz [6] ; Juliano, Maria Aparecida [6] ; de Souza Judice, Wagner Alves [1]
Total Authors: 15
Affiliation:
[1] Univ Mogi das Cruzes, Ctr Interdisciplinar Invest Bioquim, BR-08780911 Mogi Das Cruzes, SP - Brazil
[2] Univ Fed Alfenas, Fac Ciencias Farmaceut, Lab Modelagem Mol & Simulacao Computac, BR-37130001 Alfenas, MG - Brazil
[3] Univ Fed Alfenas, Lab Pesquisa Quim Med, BR-37133840 Alfenas, MG - Brazil
[4] Univ Fed Vicosa, Lab Sintese Agroquim, BR-36570900 Vicosa, MG - Brazil
[5] Univ Fed Sao Paulo, Dept Bioquim, Escola Paulista Med, BR-04044020 Sao Paulo, SP - Brazil
[6] Univ Fed Sao Paulo, Dept Biofis, Escola Paulista Med, BR-04044020 Sao Paulo, SP - Brazil
Total Affiliations: 6
Document type: Journal article
Source: BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS; v. 1865, n. 12 DEC 2021.
Web of Science Citations: 0
Abstract

Background: Garcinia brasiliensis is a species native to the Amazon forest. The white mucilaginous pulp is used in folk medicine as a wound healing agent and for peptic ulcer, urinary, and tumor disease treatments. The activity of the proprotein convertases (PCs) Subtilisin/Kex is associated with the development of viral, bacterial and fungal infections, osteoporosis, hyperglycemia, atherosclerosis, cardiovascular, neurodegenerative and neoplastic diseases. Methods: Morelloflavone (BF1) and semisynthetic biflavonoid (BF2, 3 and 4) from Garcinia brasiliensis were tested as inhibitor of PCs Kex2, PC1/3 and Furin, and determined IC50, K-i , human proinflammatory cytokines secretion in Caco-2 cells, mechanism of inhibition, and performed molecular docking studies. Results: Biflavonoids were more effective in the inhibition of neuroendocrine PC1/3 than mammalian Furin and fungal Kex2. BF1 presented a mixed inhibition mechanism for Kex2 and PC1, and competitive inhibition for Furin. BF4 has no good interaction with Kex2 and Furin since carboxypropyl groups results in steric hindrance to ligand-protein interactions. Carboxypropyl groups of BF4 promote steric hindrance with Kex2 and Furin, but effective in the affinity of PC1/3. BF4 was more efficient at inhibiting PCl/3 (IC50 = 1.13 mu M and K-i = 0,59 mu M, simple linear competitive mechanism of inhibition) than Kex2, Furin. Also, our results strongly suggested that BF4 also inhibits the endogenous cellular PC1/3 activity in Caco-2 cells, since PC1/3 inhibition by BF4 causes a large increase in IL-8 and IL-1 beta secretion in Caco-2 cells. Conclusions: BF4 is a potent and selective inhibitor of PC1/3. General significance: BF4 is the best candidate for further clinical studies on inhibition of PC1/3. (AU)

FAPESP's process: 14/02205-1 - Study of kinetic behavior of convertases
Grantee:Wagner Alves de Souza Júdice
Support Opportunities: Regular Research Grants