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,Biochimica et Biophysica Acta (BBA) - General Subjects

当前位置： X-MOL 学术 › BBA Gen. Subj. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

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
Biochimica et Biophysica Acta (BBA) - General Subjects ( IF 2.8 ) Pub Date : 2021-09-22 , DOI: 10.1016/j.bbagen.2021.130016
Aline Aparecida de Souza ₁ , Débora Martins de Andrade ₁ , Fábio da Silva Siqueira ₁ , Juliana Fortes Di Iorio ₁ , Marcia Paranho Veloso ₂ , Camila de Morais Coelho ₂ , Claudio Viegas Junior ₃ , Vanessa Silva Gontijo ₃ , Marcelo Henrique Dos Santos ₄ , Maria Cecília Zorél Meneghetti ₅ , Helena Bonciani Nader ₅ , Ivarne Luis Dos Santos Tersariol ₆ , Luiz Juliano ₇ , Maria Aparecida Juliano ₇ , Wagner Alves de Souza Judice ₁

Affiliation

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 μM and K_i = 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.

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.

中文翻译：

Semysinthetic 双黄酮类 Morelloflavone-7,4′,7″,3‴,4‴-penta-O-butanoyl 是比 Kex2 和 Furin 更有效的前蛋白转化酶 Subtilisin/Kexin PC1/3 抑制剂

背景

巴西藤黄 (Garcinia brasiliensis)是一种原产于亚马逊森林的物种。白色粘液浆在民间医学中用作伤口愈合剂以及消化性溃疡、泌尿系统疾病和肿瘤疾病的治疗。前蛋白转化酶 (PC) 枯草杆菌蛋白酶/Kex 的活性与病毒、细菌和真菌感染、骨质疏松症、高血糖、动脉粥样硬化、心血管、神经退行性和肿瘤疾病的发生有关。

方法

测试了来自巴西藤黄果的莫雷洛黄酮 (BF1) 和半合成双类黄酮 (BF2、3 和 4) 作为 PC Kex2、PC1/3 和 Furin 的抑制剂，并测定了 IC ₅₀ 、 K 、Caco-2 细胞中人类促炎细胞因子的分泌、机制抑制，并进行分子对接研究。

结果

双黄酮类化合物在抑制神经内分泌 PC1/3 方面比哺乳动物 Furin 和真菌 Kex2 更有效。 BF1 对 Kex2 和 PC1 呈现混合抑制机制，对 Furin 呈现竞争性抑制机制。 BF4 与 Kex2 和 Furin 没有良好的相互作用，因为羧丙基会导致配体-蛋白质相互作用的空间位阻。 BF4 的羧丙基可促进与 Kex2 和 Furin 的空间位阻，但对 PC1/3 的亲和力有效。 BF4 比 Kex2、弗林蛋白酶更有效地抑制 PCl/3（IC ₅₀ = 1.13 μM 和K = 0,59 μM，简单的线性竞争抑制机制）。此外，我们的结果强烈表明，BF4 还抑制 Caco-2 细胞中的内源性细胞 PC1/3 活性，因为 BF4 抑制 PC1/3 会导致 Caco-2 细胞中 IL-8 和 IL-1β 分泌大量增加。