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

• Published in: Biochimica et biophysica acta. General subjects Vol. 1865; no. 12; p. 130016
• Main Authors: de Souza, Aline Aparecida, de Andrade, Débora Martins, Siqueira, Fábio da Silva, Di Iorio, Juliana Fortes, Veloso, Marcia Paranho, Coelho, Camila de Morais, Viegas Junior, Claudio, Gontijo, Vanessa Silva, dos Santos, Marcelo Henrique, Meneghetti, Maria Cecília Zorél, Nader, Helena Bonciani, Tersariol, Ivarne Luis dos Santos, Juliano, Luiz, Juliano, Maria Aparecida, Judice, Wagner Alves de Souza
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2021
• Subjects: atherosclerosis; Biflavonoids - chemistry; Biflavonoids - pharmacology; Caco-2 Cells; flavonoids; forests; fungi; Furin - antagonists & inhibitors; Furin - metabolism; Garcinia brasiliensis; Humans; hyperglycemia; indigenous species; Inhibition mechanism; interleukin-8; Molecular Docking Simulation; Morelloflavone; neoplasms; osteoporosis; peptic ulcers; Proprotein Convertases - antagonists & inhibitors; Proprotein Convertases - metabolism; Proprotein Convertases subtilisin/kexin; pulp; secretion; Semisynthetic derivative biflanovoids; subtilisin; traditional medicine; Garcinia brasiliensis; Semisynthetic derivative biflanovoids; Caco-2 cells; Morelloflavone; Inhibition mechanism; Proprotein Convertases subtilisin/kexin
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2021.130016

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. 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, Ki, human proinflammatory cytokines secretion in Caco-2 cells, mechanism of inhibition, and performed molecular docking studies. 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 μM and Ki = 0,59 μM, 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-1β secretion in Caco-2 cells. BF4 is a potent and selective inhibitor of PC1/3. BF4 is the best candidate for further clinical studies on inhibition of PC1/3. [Display omitted] •Biflavonoids from Garcinia brasiliensis are able to inhibit proprotein convertases.•Semisynthetic biflavonoid BF4 is a potent inhibitor of PC1/3 protease.•BF4 do not perform good molecular interactions with Kex2 and Furin.•BF4 increase pro-inflammatory IL-8 and IL-β1 secretion in Caco-2 cells.•Medicinal plants are a source of molecules against pathologies involving PCs.