Novel glucagon- and OXM-based peptides acting through glucagon and GLP-1 receptors with body weight reduction and anti-diabetic properties
Novel glucagon- and OXM-based peptides acting through glucagon and GLP-1 receptors with body weight reduction and anti-diabetic properties
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基于胰高血糖素和 OXM 的新型肽通过胰高血糖素和 GLP-1 受体发挥作用，具有减轻体重和抗糖尿病的特性
DOI：
10.1016/j.bioorg.2019.103538
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发表时间：
2020-01-01
影响因子：
5.1
通讯作者：
Qian, Hai
中科院分区：
文献类型：
--
作者：
Cai, Xingguang;Li, Chengye;Qian, Hai
胃泌酸调节素（OXM）是一种内源性胃肠道激素，可激活胰高血糖素样肽-1受体（GLP-1 R）和胰高血糖素受体（GCGR）。然而，OXM具有缺点，包括差的GLP-1 R激动作用以控制血糖、短的半衰期等。受OXM与胰高血糖素之间序列关系的启发，本研究将GLP-1、exenglutamine和OXM的不同C-末端残基引入胰高血糖素，得到一系列具有增强GLP-1 R活化的杂合肽。所形成的胰高血糖素-exengland杂合肽显示出比OXM更高的GLP-1 R活化特性。然后将基于胰高血糖素-exenglycin杂合肽的肽与脂肪酸侧链偶联以延长其半衰期。结果表明，活性最强的化合物16 a可刺激糖尿病小鼠胰岛素分泌，并使血糖维持在正常水平约42.6 h。16 a在糖尿病小鼠中表现出降低的HbA 1c水平，在慢性治疗测定中显著降低肥胖小鼠的体重。16 a结合了有效的GCGR/GLP-1 R活性，有可能成为肥胖和糖尿病的新治疗药物。这一发现为平衡胰高血糖素-exenoglycin杂合肽的GLP-1/GCGR效力提供了新的见解，并有助于发现新的抗糖尿病和减肥药物。
Oxyntomodulin (OXM) is an endogenous gastrointestinal hormone, which activates both the Glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR). However, OXM has shortcomings including poor GLP-1R agonism to control glycemia, short half-life and others. Inspired from the sequence relationship between OXM and glucagon, in this study, we introduced different C-terminus residues of GLP-1, exenatide and OXM to glucagon to get a series of hybrid peptides with enhanced GLP-1R activation. The formed glucagon-exenatide hybrid peptide shows higher GLP-1R activation properties than OXM. Then the peptides based on the glucagon-exenatide hybrid peptide were coupled with fatty acid side chains to prolong their half-lives. As a result, the most potent compound 16a could stimulate insulin secretion and maintain blood glucose in normal level for similar to 42.6 h in diabetic mice. 16a exhibited reduced HbA1c level in diabetic mice, lowered body weight significantly in obesity mice on chronic treatment assay. 16a, combined efficient GCGR/GLP-1R activity, is potential as novel treatment for obesity and diabetes. This finding provides new insights into balancing GLP-1/GCGR potency of glucagon-exenatide hybrid peptide and is helpful for discovery of novel anti-diabetic and bodyweight-reducing drugs.