Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates
Glucose-responsive insulin activity by covalent modification with aliphatic phenylboronic acid conjugates
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DOI：
10.1073/pnas.1424684112
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发表时间：
2015-02-24
影响因子：
11.1
通讯作者：
Anderson, Daniel G.
中科院分区：
文献类型：
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作者：
Chou, Danny Hung-Chieh;Webber, Matthew J.;Anderson, Daniel G.
自发现和分离以来，外源性胰岛素极大地改变了糖尿病患者的前景。然而，即使当患者严格遵循胰岛素方案时，由于患者经历高血糖和低血糖状态，也可能导致严重的并发症。已经开发了几种化学或遗传修饰的胰岛素，其调节胰岛素活性的药代动力学以用于个性化治疗。在这里，我们展示了一种策略，用于化学修饰的胰岛素，旨在促进持久和葡萄糖响应活性，通过掺入脂肪族结构域，以促进疏水相互作用，以及苯基硼酸葡萄糖传感。这些合成的胰岛素衍生物能够在葡萄糖激发后快速逆转糖尿病小鼠模型中的血糖，其中一些衍生物在13小时内对重复的葡萄糖激发作出反应。性能最佳的胰岛素衍生物提供了优于天然胰岛素的上级葡萄糖控制，对葡萄糖挑战的反应性优于临床使用的长效胰岛素衍生物。此外，连续葡萄糖监测显示与健康胰腺相匹配的反应性。这种胰岛素修饰的合成方法可以提供长期和葡萄糖介导的胰岛素活性，从而减少给药次数并提高胰岛素治疗的血糖控制保真度。据我们所知，所描述的工作是第一次证明葡萄糖结合修饰的胰岛素分子具有体内验证的葡萄糖响应活性。
Since its discovery and isolation, exogenous insulin has dramatically changed the outlook for patients with diabetes. However, even when patients strictly follow an insulin regimen, serious complications can result as patients experience both hyperglycemic and hypoglycemic states. Several chemically or genetically modified insulins have been developed that tune the pharmacokinetics of insulin activity for personalized therapy. Here, we demonstrate a strategy for the chemical modification of insulin intended to promote both long-lasting and glucose-responsive activity through the incorporation of an aliphatic domain to facilitate hydrophobic interactions, as well as a phenylboronic acid for glucose sensing. These synthetic insulin derivatives enable rapid reversal of blood glucose in a diabetic mouse model following glucose challenge, with some derivatives responding to repeated glucose challenges over a 13-h period. The best-performing insulin derivative provides glucose control that is superior to native insulin, with responsiveness to glucose challenge improved over a clinically used long-acting insulin derivative. Moreover, continuous glucose monitoring reveals responsiveness matching that of a healthy pancreas. This synthetic approach to insulin modification could afford both long-term and glucose-mediated insulin activity, thereby reducing the number of administrations and improving the fidelity of glycemic control for insulin therapy. The described work is to our knowledge the first demonstration of a glucose-binding modified insulin molecule with glucose-responsive activity verified in vivo.