Site-specific fatty chain-modified exenatide analogs with balanced glucoregulatory activity and prolonged in vivo activity

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• 作者：Lidan Sun^a ; ¹ ; Xun Huang^b ; ¹ ; Jing Han^a ; ^c ; Xingguang Cai^a ; Yuxuan Dai^a ; Yingying Chu^a ; Chuandong Wang^d ; Wenlong Huang^a ; ^{ydhuangwenlong@126.com" class="auth_mail" title="E-mail the corresponding author} ; Hai Qian^a ; ^{qianhai24@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Ex-4 ; exendin-4 ; T2DM ; type 2 diabetes mellitus ; GLP-1 ; glucagon-like peptide-1 ; DPP IV ; dipeptidyl peptidase IV ; STZ ; streptozotocin ; DIO ; diet induced obesity ; PEG ; polyethylene glycol ; HSA ; human serum albumin ; UPLC&ndash ; MS ; ultra performance liquid chromatography&ndash ; mass spectrometry ; RP-HPLC ; reversed phase high-performance liquid chromatography ; cAMP ; cyclic adenosine monophosphate ; OGTT ; oral glucose tolerance test ; AUC ; area under the curve ; IPGTT ; intraperitoneal glucose tolerance t
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 June 2016
• 年：2016
• 卷：110-111
• 期：Complete
• 页码：80-91
• 全文大小：3585 K

文摘

The therapeutic utility of exenatide (Ex-4) is limited due to short plasma half-life of 2.4 h and thus numerous approaches have been used to obtain a longer action time. However, such strategies often attend to one thing and lose another. The study aimed to identify a candidate with balanced glucoregulatory activity and prolonged in vivo activity. A series of fatty chain conjugates of Ex-4 were designed and synthesized. First, thirteen cysteine modified peptides (1–13) were prepared. Peptides 1, 10, and 13 showed improved glucagon-like peptide-1 (GLP-1) receptor activate potency and were thus selected for second step modifications to yield conjugates I-1–I-9. All conjugates retained significant GLP-1 receptor activate potency and more importantly exerted enhanced albumin-binding properties and in vitro plasma stability. The protracted antidiabetic effects of the most stable I-3 were further confirmed by both multiple intraperitoneal glucose tolerance test and hypoglycemic efficacies test in vivo. Furthermore, once daily injection of I-3 to streptozotocin (STZ) induced diabetic mice achieved long-term beneficial effects on hemoglobin A1C (HbA1C) lowering and glucose tolerance. Once daily injection of I-3 to diet induced obesity (DIO) mice also achieved favorable effects on food intake, body weight, and blood chemistry. Our results suggested that I-3 was a promising agent deserving further investigation to treat obesity patients with diabetes.