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 γ-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.

中文翻译：

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定点麦考酚酸修饰的非洲爪蟾胰高血糖素样肽-1类似物的合成和药物表征

为了开发新型的长效抗糖尿病药，麦考酚酸（MPA）用于通过γ-谷氨酰基连接子在三个Lys残基上修饰非洲爪蟾胰高血糖素样肽-1类似物（GLP-1）（1）。类似地，具有不同脂肪链长度的6-氨基己酸和12-氨基月桂酸被用作MPA衍生物，然后与1缀合。通过使用适当的保护和脱保护策略，可以直接在树脂上完成合成过程以最大程度地减少副反应，从而获得了9种MPA修饰的1衍生物（2a–2i）。化合物2b和2c选择具有高GLP-1受体激活能力和降低葡萄糖活性的化合物，对其进行进一步的C末端修饰，以改善其稳定性和生物活性，从而获得化合物3a–3d。3a–3d的受体激活能力和降血糖活性与利拉鲁肽相当。理化和体外稳定性测试表明，MPA偶联可增强白蛋白结合能力，这可通过3a–3d稳定性的提高来体现。特别是在剂量为25 nmol kg ^-1时，体内3d的抗糖尿病和促胰岛素活性与司马鲁肽相当。最后，长期服用3d对葡萄糖耐量正常化和糖化血红蛋白（HbA1c）降低具有有益作用，并且未观察到肝毒性。总之，这项研究表明，MPA衍生化是开发长效抗糖尿病肽的一种实用方法。