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Site-Specific Insulin-Trehalose Glycopolymer Conjugate by Grafting from Strategy Improves Bioactivity
ACS Macro Letters ( IF 5.8 ) Pub Date : 2018-02-20 00:00:00 , DOI: 10.1021/acsmacrolett.7b00974
Kathryn M Mansfield 1, 2 , Heather D Maynard 1, 2
Affiliation  

Insulin is an important therapeutic protein for the treatment of diabetes, but it is unstable and aggregates upon exposure to environmental stressors encountered during storage and transport. To prevent degradation of the protein in this manner and retain as much in vivo bioactivity as possible, a well-defined insulin–trehalose glycopolymer conjugate was synthesized. To accomplish this, a strategy was employed to site-specifically modify insulin with a polymerization initiator at a particular conjugation site; this also facilitated purification and characterization. Lysine of the B chain was preferentially modified by conducting the reaction at high pH, taking advantage of its higher nucleophilicity than the N-terminal amines. Trehalose monomer was polymerized directly from this macroinitiator to form a well-defined conjugate. Bioactivity of the site-specific conjugate was shown to be higher compared to the nonspecific conjugate and the same as the analogous site-specific poly(ethylene glycol) (PEG) conjugate, as confirmed by the insulin tolerance test (ITT) in mice. The conjugated trehalose glycopolymer also stabilized insulin to heat as measured by high-performance liquid chromatography (HPLC).

中文翻译:

通过策略嫁接的位点特异性胰岛素-海藻糖糖聚合物缀合物提高了生物活性

胰岛素是治疗糖尿病的重要治疗蛋白,但它不稳定并且在储存和运输过程中暴露于环境压力时会聚集。为了防止蛋白质以这种方式降解并尽可能保留体内生物活性,合成了一种明确的胰岛素-海藻糖糖聚合物缀合物。为了实现这一目标,采用了一种策略,用聚合引发剂在特定的结合位点对胰岛素进行位点特异性修饰。这也有利于纯化和表征。B链的赖氨酸通过在高pH值下进行反应优先进行修饰,利用其比N端胺更高的亲核性。海藻糖单体直接由该大分子引发剂聚合形成明确的缀合物。小鼠胰岛素耐受试验 (ITT) 证实,与非特异性缀合物相比,位点特异性缀合物的生物活性更高,并且与类似的位点特异性聚乙二醇 (PEG) 缀合物相同。根据高效液相色谱 (HPLC) 的测量,缀合的海藻糖糖聚合物还可以稳定胰岛素的热稳定性。
更新日期:2018-02-20
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