Corrination of a GLP-1 Receptor Agonist for Glycemic Control without Emesis
Corrination of a GLP-1 Receptor Agonist for Glycemic Control without Emesis
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DOI：
10.1016/j.celrep.2020.107768
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发表时间：
2020-06-16
期刊：
影响因子：
8.8
通讯作者：
Doyle, Robert P.
中科院分区：
文献类型：
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作者：
Borner, Tito;Workinger, Jayme L.;Doyle, Robert P.
用于治疗2型糖尿病的胰高血糖素样肽-1受体（GLP-1R）激动剂常引起恶心、呕吐，在一些患者中还会出现不希望的厌食。值得注意的是，这些行为影响是由直接中枢GLP-1R激活引起的。在这里，我们描述了一种GLP-1R激动剂的创造，它具有改良的脑外显率，可以增强GLP-1R介导的血糖控制，而不会引起呕吐。GLP-1R激动剂exendin-4 （Ex4）与二氰钴酰胺（Cbi）（一种含有维生素B12前体的corrin环）共价结合，产生“确证”Ex4结构体（Cbi-Ex4）。在麝香鼩（一种催吐哺乳动物）中收集的数据显示，Cbi-Ex4相对于Ex4有有益的作用，正如葡萄糖耐量试验中血糖反应的改善和催吐事件的显著减少所证明的那样。我们的研究结果强调了Cbi-Ex4的临床应用潜力，数百万患者寻求改善血糖控制，而没有当前GLP-1治疗的常见副作用（如呕吐）。
Glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat type 2 diabetes mellitus often produce nausea, vomiting, and in some patients, undesired anorexia. Notably, these behavioral effects are caused by direct central GLP-1R activation. Herein, we describe the creation of a GLP-1R agonist conjugate with modified brain penetrance that enhances GLP-1 R-mediated glycemic control without inducing vomiting. Covalent attachment of the GLP-1R agonist exendin-4 (Ex4) to dicyanocobinamide (Cbi), a corrin ring containing precursor of vitamin B12, produces a "corrinated" Ex4 construct (Cbi-Ex4). Data collected in the musk shrew (Suncus murinus), an emetic mammal, reveal beneficial effects of Cbi-Ex4 relative to Ex4, as evidenced by improvements in glycemic responses in glucose tolerance tests and a profound reduction of emetic events. Our findings highlight the potential for clinical use of Cbi-Ex4 for millions of patients seeking improved glycemic control without common side effects (e.g., emesis) characteristic of current GLP-1 therapeutics.