Lithocholic Acid-Based Peptide Delivery System for an Enhanced Pharmacological and Pharmacokinetic Profile of Xenopus GLP-1 Analogs
Lithocholic Acid-Based Peptide Delivery System for an Enhanced Pharmacological and Pharmacokinetic Profile of Xenopus GLP-1 Analogs
复制标题
基于石胆酸的肽递送系统，用于增强非洲爪蟾 GLP-1 类似物的药理学和药代动力学特征。
DOI：
10.1021/acs.molpharmaceut.8b00336
复制
发表时间：
2018-07-01
影响因子：
4.9
通讯作者：
Fei, Yingying
中科院分区：
文献类型：
--
作者：
Han, Jing;Chen, Xinyu;Fei, Yingying
GLP-1类似物的主要缺点是体内半衰期短。石胆酸（LCA）是人体内四种主要胆汁酸之一，具有较高的白蛋白结合率。因此，我们设想基于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。基于我们先前鉴定的非洲爪蟾GLP-1类似物（1-3），设计了一系列LCA修饰的非洲爪蟾GLP-1缀合物（4a-4 r），并进行这些缀合物的生物活性研究以鉴定具有平衡的体外受体活化效力和血浆稳定性的化合物。选择4c、4 i和4 r，并优化它们的LCA侧链以进一步增加它们的稳定性，得到5a-5c。化合物5 b显示出比4 i和利拉鲁肽更高的白蛋白亲和力和延长的体外稳定性。在db/ db小鼠中，5 b表现出与利拉鲁肽和Semaglutide相当的降血糖和促胰岛素活性。重要的是，5 b的白蛋白亲和力增强导致体内抗糖尿病持续时间延长。最后，5 b的长期治疗研究证明了5 b对db/ db小鼠的HbA 1c、体重、血糖和胰腺内分泌缺陷的治疗作用。我们的研究显示5 b是一个有前途的抗糖尿病候选药物。此外，我们的研究表明，非洲爪蟾GLP-1类似物与LCA的衍生化代表了开发有效的长效GLP-1受体激动剂用于治疗2型糖尿病的有效策略。
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.