Lithocholic Acid-Based Peptide Delivery System for an Enhanced Pharmacological and Pharmacokinetic Profile of Xenopus GLP-1 Analogs,Molecular Pharmaceutics

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Lithocholic Acid-Based Peptide Delivery System for an Enhanced Pharmacological and Pharmacokinetic Profile of Xenopus GLP-1 Analogs
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-05-25 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00336
Jing Han ₁ , Xinyu Chen ₁ , Liming Zhao ₁ , Junjie Fu ₂ , Lidan Sun ₃ , Ying Zhang ₁ , Feng Zhou ₁ , Yingying Fei ₁

Affiliation

GLP-1 analogs suffer from the main disadvantage of a short in vivo half-life. Lithocholic acid (LCA), one of the four main bile acids in the human body, possesses a high albumin binding rate. We therefore envisioned that a LCA-based peptide delivery system could extend the half-life of GLP-1 analogs by facilitating the noncovalent binding of peptides to human serum albumin. On the basis of our previously identified Xenopus GLP-1 analogs (1–3), a series of LCA-modified Xenopus GLP-1 conjugates were designed (4a–4r), and the bioactivity studies of these conjugates were performed to identify compounds with balanced in vitro receptor activation potency and plasma stability. 4c, 4i, and 4r were selected, and their LCA side chains were optimized to further increase their stability, affording 5a–5c. Compound 5b showed a more increased albumin affinity and prolonged in vitro stability than that of 4i and liraglutide. In db/db mice, 5b exhibited comparable hypoglycemic and insulinotropic activity to liraglutide and semaglutide. Importantly, the enhanced albumin affinity of 5b resulted in a prolonged in vivo antidiabetic duration. Finally, chronic treatment investigations of 5b demonstrated the therapeutic effects of 5b on HbA1c, body weight, blood glucose, and pancreatic endocrine deficiencies on db/db mice. Our studies revealed 5b as a promising antidiabetic candidate. Furthermore, our study suggests the derivatization of Xenopus GLP-1 analogs with LCA represents an effective strategy to develop potent long-acting GLP-1 receptor agonists for the treatment of type 2 diabetes.

中文翻译：

基于胆酸的肽递送系统，可增强爪蟾GLP-1类似物的药理和药代动力学特性

GLP-1类似物遭受体内半衰期短的主要缺点。胆酸（LCA）是人体内四种主要的胆汁酸之一，具有很高的白蛋白结合率。因此，我们设想了基于LCA的肽递送系统可以通过促进肽与人血清白蛋白的非共价结合来延长GLP-1类似物的半衰期。上的基础我们的先前鉴定的爪蟾GLP-1类似物（1 - 3），一系列LCA改性的非洲爪蟾的GLP-1共轭物设计（图4a - 4R），和这些共轭物的生物活性进行研究以鉴定与化合物平衡了体外受体激活能力和血浆稳定性。选择了4c，4i和4r，并对它们的LCA侧链进行了优化，以进一步提高其稳定性，从而得到5a - 5c。与4i和利拉鲁肽相比，化合物5b显示出更高的白蛋白亲和力并延长了体外稳定性。在db / db小鼠中，5b表现出与利拉鲁肽和司马鲁肽相当的降血糖和促胰岛素活性。重要的是，5b增强的白蛋白亲和力导致体内抗糖尿病持续时间延长。最后，对5b的慢性治疗研究证明了5b的治疗作用db / db小鼠的HbA1c，体重，血糖和胰腺内分泌缺陷的5b值。我们的研究表明5b是有前途的抗糖尿病药物。此外，我们的研究表明，用LCA对非洲爪蟾GLP-1类似物的衍生化是开发有效的长效GLP-1受体激动剂用于治疗2型糖尿病的有效策略。

更新日期：2018-05-25

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