Synthesis and pharmaceutical characterization of site specific mycophenolic acid-modified Xenopus glucagon-like peptide-1 analogs
Synthesis and pharmaceutical characterization of site specific mycophenolic acid-modified Xenopus glucagon-like peptide-1 analogs
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位点特异性霉酚酸修饰的爪蟾胰高血糖素样肽-1 类似物的合成和药物表征
DOI：
10.1039/c7md00471k
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发表时间：
2018-01-01
期刊：
影响因子：
--
通讯作者：
Zhu, Ke
中科院分区：
文献类型：
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作者：
Han, Jing;Fu, Junjie;Zhu, Ke
为了开发新型长效降糖药物，利用霉酚酸(MPA)通过γ-谷氨酰键修饰非洲爪哇胰升糖素样肽-1类似物(GLP-1)(1)。同样，以不同脂肪链长度的6-氨基己酸和12-氨基月桂酸作为MPA的衍生物，然后与1偶联，通过适当的保护和去保护策略，直接在树脂上完成合成过程，最大限度地减少副反应，得到9个MPA修饰的1，2，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4化合物2b和2c具有较高的GLP-1受体活性和降糖活性，通过进一步的C-末端修饰来提高其稳定性和生物活性，得到化合物3a-3d。3a-3d的受体激活能力和降血糖活性与利拉鲁肽相当。物理化学和体外稳定性测试表明，MPA偶联导致白蛋白结合能力增强，这反映在3a-3D稳定性的改善上。尤其是在25nmoL·kg~(-1)剂量下，3D的体内降糖和促胰岛素活性与半谷氨酸相当。最后，长期服用3D在糖耐量正常化和降低糖化血红蛋白(HbA1c)方面取得了有益的效果，并且没有观察到肝脏毒性。综上所述，本研究证明了甲孕酮衍生化是开发长效降糖肽的一种可行的方法。
To develop novel long-acting antidiabetic agents, mycophenolic acid (MPA) was used to modify Xenopus glucagon-like peptide-1 analog (GLP-1) (1) at three Lys residues through a gamma-glutamyl linker. Similarly, 6-aminocaproic acid and 12-aminolauric acid with different lengths of fatty chain were used as MPA derivatives which were then conjugated with 1. By using proper protection and deprotection strategies, the synthetic process was completed directly on the resin to minimize the side reactions, and nine MPA-modified 1 derivatives (2a-2i) were obtained. Compounds 2b and 2c, which showed high GLP-1 receptor activation potencies and glucose lowering activities, were selected for further C-terminal modification to improve their stabilities and bioactivities, giving compounds 3a-3d. The receptor activation potencies and hypoglycemic activities of 3a-3d were comparable to that of liraglutide. Physicochemical and in vitro stability tests revealed that MPA conjugation led to enhanced albumin binding abilities as reflected by the improved stabilities of 3a-3d. In particular, at a dose of 25 nmol kg(-1), the in vivo antidiabetic and insulinotropic activities of 3d were comparable to those of semaglutide. Finally, long-term administration of 3d achieved beneficial effects on glucose tolerance normalization and glycated hemoglobin (HbA1c) lowering, and no hepatotoxicity was observed. In conclusion, this research demonstrated that MPA derivatization was a practical way to develop long-acting antidiabetic peptides.