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Byproduct-Free Intact Modification of Insulin by Cholesterol End-Modified Poly(ethylene glycol) for in Vivo Protein Delivery
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-12-20 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00593 Shoichiro Asayama 1 , Kana Nagashima 1 , Yoichi Negishi 2 , Hiroyoshi Kawakami 1
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-12-20 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00593 Shoichiro Asayama 1 , Kana Nagashima 1 , Yoichi Negishi 2 , Hiroyoshi Kawakami 1
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Insulin is a key peptide hormone used for the treatment of both type I and type II diabetes. To maximize the effect of the treatment of these diseases, the addition of poly(ethylene glycol) (PEGylation) methods for the insulin are widely developed. Here, to make these PEGylation methods the simplest, we report the byproduct-free intact modification of insulin by cholesterol end-modified poly(ethylene glycol) with urethane, propyl, and methoxy groups (that is, Chol–U–Pr–mPEG). The noncovalent PEGylation by the Chol–U–Pr–mPEG has been achieved by the simple mixing of insulin with the Chol–U–Pr–mPEG in aqueous solution, followed by freeze-drying. The formation of the Chol–U–Pr–mPEG/insulin complex has proceeded without byproducts, such as N-hydroxysuccinimide, formed by the conventional covalent PEGylation using an active ester group. The byproduct-free PEGylation has preserved insulin conformation as well as primary structure. The intact PEGylation has protected insulin from hydrolysis by protease. The resulting insulin modified by the Chol–U–Pr–mPEG has sustainably suppressed the level of blood glucose, as compared to naked insulin, in mice. Consequently, the Chol–U–Pr–mPEG/insulin complex formation offers the byproduct-free intact PEGylation of insulin for in vivo protein delivery.
中文翻译：
胆固醇末端修饰的聚乙二醇用于体内蛋白的无副产物的胰岛素完整修饰
胰岛素是用于治疗I型和II型糖尿病的关键肽激素。为了使这些疾病的治疗效果最大化，广泛开发了针对胰岛素添加聚乙二醇（PEGylation）的方法。在这里，为了使这些PEG化方法最简单，我们报道了胆固醇端基修饰的具有氨基甲酸乙酯，丙基和甲氧基的聚乙二醇对胰岛素的无副产物的完整修饰（即Chol–U–Pr–mPEG） 。通过将胰岛素与Chol-U-Pr-mPEG水溶液简单混合，然后冷冻干燥，可以实现Chol-U-Pr-mPEG的非共价PEG化。Chol–U–Pr–mPEG /胰岛素复合物的形成过程在没有副产物（例如N）的情况下进行-羟基琥珀酰亚胺，通过使用活性酯基团的常规共价PEG化反应形成。无副产物的聚乙二醇化保留了胰岛素的构象以及一级结构。完整的PEG化可保护胰岛素不受蛋白酶水解。与裸胰岛素相比，经Chol–U–Pr–mPEG修饰的胰岛素与小鼠的裸露胰岛素相比，能够持续抑制血糖水平。因此，Chol–U–Pr–mPEG /胰岛素复合物的形成为体内蛋白质递送提供了无副产物的完整胰岛素胰岛素。
更新日期：2017-12-20
中文翻译：
胆固醇末端修饰的聚乙二醇用于体内蛋白的无副产物的胰岛素完整修饰
胰岛素是用于治疗I型和II型糖尿病的关键肽激素。为了使这些疾病的治疗效果最大化，广泛开发了针对胰岛素添加聚乙二醇（PEGylation）的方法。在这里，为了使这些PEG化方法最简单，我们报道了胆固醇端基修饰的具有氨基甲酸乙酯，丙基和甲氧基的聚乙二醇对胰岛素的无副产物的完整修饰（即Chol–U–Pr–mPEG） 。通过将胰岛素与Chol-U-Pr-mPEG水溶液简单混合，然后冷冻干燥，可以实现Chol-U-Pr-mPEG的非共价PEG化。Chol–U–Pr–mPEG /胰岛素复合物的形成过程在没有副产物（例如N）的情况下进行-羟基琥珀酰亚胺，通过使用活性酯基团的常规共价PEG化反应形成。无副产物的聚乙二醇化保留了胰岛素的构象以及一级结构。完整的PEG化可保护胰岛素不受蛋白酶水解。与裸胰岛素相比，经Chol–U–Pr–mPEG修饰的胰岛素与小鼠的裸露胰岛素相比，能够持续抑制血糖水平。因此，Chol–U–Pr–mPEG /胰岛素复合物的形成为体内蛋白质递送提供了无副产物的完整胰岛素胰岛素。
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