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Targeting the insulin receptor with hormone and peptide dimers
Journal of Peptide Science ( IF 1.8 ) Pub Date : 2022-11-06 , DOI: 10.1002/psc.3461 Jingjing Lin 1, 2 , Irena Selicharová 1 , Katarína Mitrová 1 , Benjamin Fabre 1 , Vijay Madhav Miriyala 1, 3 , Martin Lepšík 1 , Jiří Jiráček 1 , María Soledad Garre Hernández 1
Journal of Peptide Science ( IF 1.8 ) Pub Date : 2022-11-06 , DOI: 10.1002/psc.3461 Jingjing Lin 1, 2 , Irena Selicharová 1 , Katarína Mitrová 1 , Benjamin Fabre 1 , Vijay Madhav Miriyala 1, 3 , Martin Lepšík 1 , Jiří Jiráček 1 , María Soledad Garre Hernández 1
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Insulin is a key hormone involved in the regulation of overall energetic homeostasis of the organism. The dimeric character of the receptor for insulin evokes ideas about its activation or inhibition with peptide dimers that could either trigger or block the structural transition of the insulin receptor, leading to its activation. Herewith, we present the chemical engineering and biological characterization of several series of insulin dimers or dimers of specific peptides that should be able to bind receptors for insulin or insulin growth factor 1. The hormones or peptides in the dimers were interconnected with different linkers, consisting of triazole moieties and 3, 6, 8, 11, or 23 polyethylene glycol units. The prepared dimers were weaker in binding to insulin receptors than human insulin. However, some of the insulin dimers showed preferential binding specificity toward the isoform A of the insulin receptor, and the insulin dimers also stimulated the insulin receptor more strongly than would be consistent with their binding affinities. Our results suggest that designing insulin dimers may be a promising strategy for modulating the ability of the hormone to activate the receptor or to alter its specificity toward insulin receptor isoforms.
中文翻译：
用激素和肽二聚体靶向胰岛素受体
胰岛素是参与调节机体整体能量稳态的关键激素。胰岛素受体的二聚体特性让人联想到它被肽二聚体激活或抑制，肽二聚体可以触发或阻断胰岛素受体的结构转变，从而导致其激活。在此，我们介绍了几个系列的胰岛素二聚体或特定肽二聚体的化学工程和生物学特性，它们应该能够结合胰岛素或胰岛素生长因子 1 的受体。二聚体中的激素或肽与不同的接头相互连接，包括三唑部分和 3、6、8、11 或 23 个聚乙二醇单元。制备的二聚体与胰岛素受体的结合弱于人胰岛素。然而，一些胰岛素二聚体显示出对胰岛素受体亚型 A 的优先结合特异性，并且胰岛素二聚体还比与其结合亲和力一致的更强烈地刺激胰岛素受体。我们的结果表明，设计胰岛素二聚体可能是一种很有前途的策略，可用于调节激素激活受体的能力或改变其对胰岛素受体亚型的特异性。
更新日期：2022-11-06
中文翻译：
用激素和肽二聚体靶向胰岛素受体
胰岛素是参与调节机体整体能量稳态的关键激素。胰岛素受体的二聚体特性让人联想到它被肽二聚体激活或抑制，肽二聚体可以触发或阻断胰岛素受体的结构转变，从而导致其激活。在此，我们介绍了几个系列的胰岛素二聚体或特定肽二聚体的化学工程和生物学特性，它们应该能够结合胰岛素或胰岛素生长因子 1 的受体。二聚体中的激素或肽与不同的接头相互连接，包括三唑部分和 3、6、8、11 或 23 个聚乙二醇单元。制备的二聚体与胰岛素受体的结合弱于人胰岛素。然而，一些胰岛素二聚体显示出对胰岛素受体亚型 A 的优先结合特异性，并且胰岛素二聚体还比与其结合亲和力一致的更强烈地刺激胰岛素受体。我们的结果表明，设计胰岛素二聚体可能是一种很有前途的策略，可用于调节激素激活受体的能力或改变其对胰岛素受体亚型的特异性。
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