An Aldehyde Responsive, Cleavable Linker for Glucose Responsive Insulins
An Aldehyde Responsive, Cleavable Linker for Glucose Responsive Insulins
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DOI：
10.1002/chem.202004878
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发表时间：
2021-01-15
影响因子：
4.3
通讯作者：
Jensen, Knud J.
中科院分区：
文献类型：
--
作者：
Mannerstedt, Karin;Mishra, Narendra Kumar;Jensen, Knud J.
响应于血糖浓度变化的葡萄糖响应性胰岛素（GRI）仍然是一个难以实现的目标。在这里，我们描述了基于腙和噻唑烷结构的葡萄糖可裂解接头的发展。我们开发了具有低水平的自发水解但随着葡萄糖浓度的升高水解水平增加的接头，这证明了它们在体外的葡萄糖响应性。通过pH控制的酰化将脂化的腙和噻唑烷缀合至HI的LysB29侧链，提供具有噻唑烷体外证实的葡萄糖响应性的GRI。钳夹研究显示，在高血糖条件下，一种GRI的葡萄糖输注增加，表明了真正的葡萄糖反应。这些GRI中的葡萄糖响应性可切割接头允许葡萄糖水平的变化以驱动活性胰岛素从循环贮库中释放。我们已经证明了一个前所未有的，化学响应连接器的生物制药概念。
A glucose responsive insulin (GRI) that responds to changes in blood glucose concentrations has remained an elusive goal. Here we describe the development of glucose cleavable linkers based on hydrazone and thiazolidine structures. We developed linkers with low levels of spontaneous hydrolysis but increased level of hydrolysis with rising concentrations of glucose, which demonstrated their glucose responsiveness in vitro. Lipidated hydrazones and thiazolidines were conjugated to the LysB29 side-chain of HI by pH-controlled acylations providing GRIs with glucose responsiveness confirmed in vitro for thiazolidines. Clamp studies showed increased glucose infusion at hyperglycemic conditions for one GRI indicative of a true glucose response. The glucose responsive cleavable linker in these GRIs allow changes in glucose levels to drive the release of active insulin from a circulating depot. We have demonstrated an unprecedented, chemically responsive linker concept for biopharmaceuticals.