Micellar Nanomedicine of Novel Fatty Acid Modified Xenopus Glucagon-like Peptide-1: Improved Physicochemical Characteristics and Therapeutic Utilities for Type 2 Diabetes
Micellar Nanomedicine of Novel Fatty Acid Modified Xenopus Glucagon-like Peptide-1: Improved Physicochemical Characteristics and Therapeutic Utilities for Type 2 Diabetes
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新型脂肪酸修饰爪蟾胰高血糖素样肽-1的胶束纳米药物：改善2型糖尿病的理化特性和治疗效用
DOI：
10.1021/acs.molpharmaceut.7b00632
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发表时间：
2017-11-01
影响因子：
4.9
通讯作者：
Fu, Junjie
中科院分区：
文献类型：
--
作者：
Han, Jing;Fei, Yingying;Fu, Junjie
为了开发治疗效果更好的新型长效抗糖尿病药物，通过GLP-1、Xen-GLP-1B、exendin-4和lixisenatide的关键序列的杂交，构建了两个GLP-1类似物。杂交体1和杂交体2在体外和体内表现出增强的生物活性，并进一步在赖氨酸残基上被定点脂化，以实现更长的作用时间和更少的给药频率。与天然多肽相比，化合物3-6具有相似的体外活性，但由于其在体内的水溶性降低和吸收迟缓，降低了体内的急性降糖活性。为了避免这些问题，选择了化合物3(异谷氨酸)与空间稳定的胶束(SSM)进行自缔合。自缔合SSM后，异亮氨酸的α-螺旋结构和溶解度显著提高。值得注意的是，异亮氨酸-SSM的物理化学性质的改善导致了急性降糖能力的恢复，而不影响其长期的降糖活性。最重要的是，临床前研究表明，异谷氨酸-SSM在糖尿病db/db小鼠中的治疗效果和安全性得到了改善。我们的工作表明，SSM掺入是改善疏水性多肽药物的药代动力学和生物学性质的有效途径。此外，我们的数据显示，异源谷氨酸SSM是一种治疗2型糖尿病的新型纳米药物。
To develop novel long-acting antidiabetics with improved therapeutic efficacy, two glucagon-like peptide-1 (GLP-1) analogs were constructed through the hybridization of key sequences of GLP-1, xenGLP-1B, exendin-4, and lixisenatide. Hybrids 1 and 2 demonstrated enhanced in vitro and in vivo biological activities and were further site-specifically lipidized at lysine residues to achieve prolonged duration of action and less frequent administration. Compared with their native peptides, compounds 3-6 showed similar in vitro activities but impaired in vivo acute hypoglycemic potencies due to decreased aqueous solubility and retarded absorption in vivo. To circumvent these issues, compound 3 (xenoglutide) was selected to be self-associated with sterically stabilized micelles (SSM). The alpha-helix and solubility of xenoglutide were significantly improved after self-associated with SSM. Notably, the improved physicochemical characteristics of xenoglutide-SSM led to revival of acute hypoglycemic ability without affecting its long-term glucose-lowering activity. Most importantly, preclinical studies demonstrated improved therapeutic effects and safety of xenoglutide-SSM in diabetic db/db mice. Our work suggests the SSM incorporation as an effective approach to improve the pharmacokinetic and biological properties of hydrophobicity peptide drugs. Furthermore, our data dearly indicate xenoglutideSSM as a novel nanomedicine for the treatment of type 2 diabetics.