Discovery of lixisenatide analogues as long-acting hypoglycemic agents using novel peptide half-life extension technology based on mycophenolic acid.
Discovery of lixisenatide analogues as long-acting hypoglycemic agents using novel peptide half-life extension technology based on mycophenolic acid.
复制标题
使用基于霉酚酸的新型肽半衰期延长技术发现利西拉来类似物作为长效降血糖药
作者：
多肽与人血清白蛋白的非共价结合可防止肾脏清除和酶降解。在此，我们研究了霉酚酸(MPA)白蛋白结合剂对提高多肽稳定性的效果。为了验证原理，选择了短效GLP-1受体激动剂利昔那肽，并用不同的MPA白蛋白结合剂对其进行功能化处理。在体外，所有利昔那肽类似物都显示出良好的GLP-1受体激活效力。高效亲和层析(HPAC)和超滤分析表明，DiMPA能够使白蛋白与利塞那肽有较高的亲和力，并表明含有OEG间隔基的DiMPA修饰的利塞那提类似物的亲和力增强。在db/db小鼠中，所选择的多肽2c在降糖和促胰岛素活性方面显示出与利塞那肽相当的效果。此外，在db/db小鼠中，2c的葡萄糖稳态作用时间与Semagluted相当。更重要的是，在正常昆明种小鼠给药2周后，2c组和半谷氨酸组的毒性指数与利西塞那肽相似，说明Dipa白蛋白结合剂没有明显的毒性作用。在db/db小鼠上进行的短期研究(21天)表明，2c对胰岛的保护作用优于四氢呋喃。重要的是，在对db/db小鼠的慢性研究中(84天)，2c在血糖控制方面显示出持续的改善，其程度比Semagluide更大。因此，我们建议Dipa修饰作为一种新的和通用的方法来开发用于治疗2型糖尿病的长效GLP-1受体激动剂，并建议2c作为一种有前途的抗糖尿病候选药物。
Noncovalent binding of peptides to human serum albumin protects against renal clearance and enzymatic degradation. Herein, we investigated the effect of mycophenolic acid (MPA) albumin binders for improving the stability of peptides. For proof-of-principle, the short acting glucagon-like peptide-1 (GLP-1) receptor agonist lixisenatide was selected and functionalized with different MPA albumin binders. In vitro, all lixisenatide analogues showed well preserved GLP-1 receptor activation potency. High performance affinity chromatography (HPAC) and ultrafiltration analyses indicated that DiMPA was able to confer high albumin affinity to lixisenatide and revealed that affinity is increased for DiMPA modified lixisenatide analogues containing OEG spacers. In db/db mice, the selected peptide 2c showed comparable efficacies to lixisenatide with respect to glucose-lowering and insulinotropic activities. Furthermore, the duration of action of glucose homeostasis of 2c was comparable to semaglutide in db/db mice. Importantly, DiMPA albumin binder did not bring significant toxicity of lixisenatide, as reflected by the comparable toxicity indexes in 2c and semaglutide groups after 2 weeks dosing in normal Kunming mice. Short-term study (21 days) conducted on db/db mice showed the better therapeutic efficacies of 2c than semaglutide on pancreas islets protection. Importantly, in chronic studies (84 days) on db/db mice, 2c exhibited a sustained improvement in glycaemic control, to a greater extent than that of semaglutide. Thus, we propose DiMPA modification as a novel and general method for development of long-acting GLP-1 receptor agonists for type 2 diabetes treatments, and 2c as a promising antidiabetic candidate.
登录
查看更多内容
影响因子：
4.7
作者：
Kim, Tae Hyung;Jiang, Hai Hua;Lee, Kang Choon
通讯作者：
Lee, Kang Choon
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
影响因子：
--
作者：
Han, Jing;Fu, Junjie;Zhu, Ke
通讯作者：
Zhu, Ke
DOI：
10.1124/jpet.105.083436
发表时间：
2005-08-01
影响因子：
3.5
作者：
Kapusta, DR;Thorkildsen, C;Petersen, JS
通讯作者：
Petersen, JS
两种新型长效非洲爪蟾胰高血糖素样肽-1类似物 xGLP159 和 xGLP296 的长期给药可有效改善啮齿动物模型的全身代谢和血糖控制
影响因子：
4.8
作者：
Han, Jing;Meng, Tingting;Li, Chenglin
通讯作者：
Li, Chenglin
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
影响因子：
4.9
作者：
Han, Jing;Fei, Yingying;Fu, Junjie
通讯作者：
Fu, Junjie