Human insulin-like growth factor 1 (IGF-1) is a 70 amino acid protein hormone, with key impact on growth, development, and lifespan. The physiological and clinical importance of IGF-1 prompted challenging chemical and biological trials toward the development of its analogs as molecular tools for the IGF-1 receptor (IGF1-R) studies and as new therapeutics. Here, we report a new method for the total chemical synthesis of IGF-1 analogs, which entails the solid-phase synthesis of two IGF-1 precursor chains that is followed by the Cu^I-catalyzed azide–alkyne cycloaddition ligation and by biomimetic formation of a native pattern of disulfides. The connection of the two IGF-1 precursor chains by the triazole-containing moieties, and variation of its neighboring sequences (Arg36 and Arg37), was tolerated in IGF-1R binding and its activation. These new synthetic IGF-1 analogs are unique examples of disulfide bonds’ rich proteins with intra main-chain triazole links. The methodology reported here also presents a convenient synthetic platform for the design and production of new analogs of this important human hormone with non-standard protein modifications.

中文翻译：

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在 C 域中单击的胰岛素样生长因子 1 类似物：化学合成和生物活性

人胰岛素样生长因子 1 (IGF-1) 是一种由 70 个氨基酸组成的蛋白质激素，对生长、发育和寿命具有重要影响。IGF-1 的生理和临床重要性促使开展具有挑战性的化学和生物学试验，以开发其类似物作为 IGF-1 受体 (IGF1-R) 研究的分子工具和新疗法。在这里，我们报告了一种用于 IGF-1 类似物全化学合成的新方法，该方法需要固相合成两条 IGF-1 前体链，然后是 Cu ^I催化的叠氮化物-炔烃环加成连接和通过仿生形成天然二硫化物模式。两个 IGF-1 前体链通过含三唑部分的连接，以及其相邻序列（Arg36 和 Arg37）的变化，在 IGF-1R 结合及其激活中是可容忍的。这些新的合成 IGF-1 类似物是具有主链内三唑键的富含二硫键的蛋白质的独特例子。这里报告的方法还提供了一个方便的合成平台，用于设计和生产这种具有非标准蛋白质修饰的重要人类激素的新类似物。