Insulin derivatives provide new functions that are distinctivefrom native insulin. We investigated insulin modifications on theC-terminal A chain with insulin receptor (IR) peptide binders andpresented a full and potent IR antagonist. We prepared insulin precursorsfeaturing a sortase A (SrtA) recognition sequence, LPETGG, at theC-terminal A chain and used a SrtA-mediated ligation method to synthesizeinsulin derivatives. The insulin precursor exhibits full IR agonismpotency, similar to native human insulin. We explored derivativeswith linear IR binding peptides attached to the insulin C-terminalA chain. One insulin derivative with an IR binder (Ins-AC-S2) canfully antagonize IR activation by insulin, as confirmed by cell-basedassays. This IR antagonist suppresses insulin-induced hypoglycemiain a streptozotocin-induced diabetic rat model. This study providesa new direction toward insulin antagonist development.
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机译：胰岛素衍生物提供了与天然胰岛素不同的新功能。我们用胰岛素受体 （IR） 肽结合物研究了 C 端 A 链上的胰岛素修饰，并提出了一种完整而有效的 IR 拮抗剂。我们制备了胰岛素前体，该前体在C端A链上具有分选酶A（SrtA）识别序列LPETGG，并使用SrtA介导的连接方法合成胰岛素衍生物。胰岛素前体表现出完全的 IR 激动效力，类似于天然人胰岛素。我们探索了与胰岛素 C 末端 A 链相连的线性 IR 结合肽的衍生物。一种带有 IR 结合剂的胰岛素衍生物 （Ins-AC-S2） 可以拮抗胰岛素的 IR 激活，这已通过基于细胞的测定得到证实。这种 IR 拮抗剂抑制胰岛素诱导的链脲佐菌素诱导的糖尿病大鼠模型中的低血糖。本研究为胰岛素拮抗剂的开发提供了新的方向。
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