利用低聚胆汁酸设计嵌合GLP-1A,利用转运体介导的内吞作用进行口服给药。

IF 11.3 1区 医学 Q1 Medicine
Seho Kweon, Jun-Hyuck Lee, Seong-Bin Yang, Seong Jin Park, Laxman Subedi, Jung-Hyun Shim, Seung-Sik Cho, Jeong Uk Choi, Youngro Byun, Jooho Park, Jin Woo Park
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引用次数: 0

摘要

背景:尽管胰高血糖素样肽-1激动剂(GLP-1A)治疗糖尿病有效,但其大分子量和高亲水性导致细胞渗透性差,从而限制了其口服生物利用度。为了解决这个问题,我们开发了一种嵌合GLP-1A,其靶向转运蛋白介导的内吞作用,通过利用肠道中可用的转运蛋白,特别是根尖钠依赖性胆汁酸转运蛋白(ASBT),增强细胞对GLP-1A的通透性。方法:采用分子对接和分子动力学模拟的方法研究单、双、四脱氧胆酸(DOCA)(单、双、四脱氧胆酸)与ASBT的结合作用。利用马来酰亚胺反应合成嵌合glp - 1a共轭低聚物DOCAs (mD-G1A、bD-G1A和tD-G1A)后,评估其体外细胞通透性和胰岛素调节作用。并对其在大鼠体内的口服吸收及对糖尿病db/db小鼠模型的降糖作用进行了评价。结果:实验结果表明,tetraDOCA具有最低的相互作用能,与ASBT具有较高的结合亲和力。glp - 1a偶联寡聚doca的胰岛素促胰岛素作用与GLP-1A-Cys或艾塞那肽没有区别。此外,bD-G1A和tD-G1A均表现出较好的体外Caco-2细胞通透性和较高的体内生物利用度(分别为7.58%和8.63%)。在对db/db小鼠的降糖作用方面,与对照组相比,tD-G1A (50 μg/kg)比bD-G1A (50 μg/kg)更能降低葡萄糖水平(35.5%比26.4%)。结论:GLP-1A与低聚doca偶联,所得到的嵌合化合物不仅具有胰高血糖素样肽-1受体激动剂活性,而且具有口服给药的潜力。这些发现表明,低聚doca可以作为GLP-1A口服给药的有效载体,为提高GLP-1A的口服生物利用度和改善糖尿病治疗提供了一个有希望的解决方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery.

Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery.

Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery.

Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery.

Background: Despite the effectiveness of glucagon-like peptide-1 agonist (GLP-1A) in the treatment of diabetes, its large molecular weight and high hydrophilicity result in poor cellular permeability, thus limiting its oral bioavailability. To address this, we developed a chimeric GLP-1A that targets transporter-mediated endocytosis to enhance cellular permeability to GLP-1A by utilizing the transporters available in the intestine, particularly the apical sodium-dependent bile acid transporter (ASBT).

Methods: In silico molecular docking and molecular dynamics simulations were used to investigate the binding interactions of mono-, bis-, and tetra-deoxycholic acid (DOCA) (monoDOCA, bisDOCA, and tetraDOCA) with ASBT. After synthesizing the chimeric GLP-1A-conjugated oligomeric DOCAs (mD-G1A, bD-G1A, and tD-G1A) using a maleimide reaction, in vitro cellular permeability and insulinotropic effects were assessed. Furthermore, in vivo oral absorption in rats and hypoglycemic effect on diabetic db/db mice model were evaluated.

Results: In silico results showed that tetraDOCA had the lowest interaction energy, indicating high binding affinity to ASBT. Insulinotropic effects of GLP-1A-conjugated oligomeric DOCAs were not different from those of GLP-1A-Cys or exenatide. Moreover, bD-G1A and tD-G1A exhibited improved in vitro Caco-2 cellular permeability and showed higher in vivo bioavailability (7.58% and 8.63%) after oral administration. Regarding hypoglycemic effects on db/db mice, tD-G1A (50 μg/kg) lowered the glucose level more than bD-G1A (50 μg/kg) compared with the control (35.5% vs. 26.4%).

Conclusion: GLP-1A was conjugated with oligomeric DOCAs, and the resulting chimeric compound showed the potential not only for glucagon-like peptide-1 receptor agonist activity but also for oral delivery. These findings suggest that oligomeric DOCAs can be used as effective carriers for oral delivery of GLP-1A, offering a promising solution for enhancing its oral bioavailability and improving diabetes treatment.

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来源期刊
Biomaterials Research
Biomaterials Research Medicine-Medicine (miscellaneous)
CiteScore
10.20
自引率
3.50%
发文量
63
审稿时长
30 days
期刊介绍: Biomaterials Research, the official journal of the Korean Society for Biomaterials, is an open-access interdisciplinary publication that focuses on all aspects of biomaterials research. The journal covers a wide range of topics including novel biomaterials, advanced techniques for biomaterial synthesis and fabrication, and their application in biomedical fields. Specific areas of interest include functional biomaterials, drug and gene delivery systems, tissue engineering, nanomedicine, nano/micro-biotechnology, bio-imaging, regenerative medicine, medical devices, 3D printing, and stem cell research. By exploring these research areas, Biomaterials Research aims to provide valuable insights and promote advancements in the biomaterials field.
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