Recombinant Insulin-Like Growth Factor 1 Dimers: Receptor Binding Affinities and Activation Abilities.
Recombinant Insulin-Like Growth Factor 1 Dimers: Receptor Binding Affinities and Activation Abilities.
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DOI：
10.1007/s10989-023-10499-1
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发表时间：
2023
影响因子：
2.5
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中科院分区：
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胰岛素样生长因子1 （IGF-1）及其受体（IGF-1R）是一个重要的生物系统，参与调节正常生长，但也被认为在癌症中发挥作用。IGF-1R拮抗剂作为IGF-1R酪氨酸激酶抑制剂或抗IGF-1R单克隆抗体的替代品，其潜在的抗增殖特性可能是有趣的。在这项研究中，我们受到胰岛素二聚体的成功开发的启发，该二聚体能够通过同时结合两个分离的结合位点并阻断胰岛素受体的结构重排来拮抗胰岛素对胰岛素受体（IR）的影响。我们在大肠杆菌中设计并生产了三种不同的IGF-1二聚体，其中IGF-1单体通过它们的N和c端相互连接，连接体有8、15或25个氨基酸。我们发现重组产物容易形成错误折叠或减少变体，但其中一些能够以低纳摩尔亲和力结合IGF-1R，并且它们都能按其结合亲和力成比例激活IGF-1R。总的来说，我们的工作可以被认为是一项先导研究，尽管它没有导致新的IGF-1R拮抗剂的发现，但它探索了重组生产IGF-1二聚体的可能性，并导致了活性化合物的制备。这项工作可以激发进一步的研究，例如，制备IGF-1与特定蛋白质的结合物，用于激素及其受体的研究或治疗应用。在线版本包含补充材料，可在10.1007/s10989-023-10499-1获得。
Insulin-like growth factor 1 (IGF-1) and its IGF-1 receptor (IGF-1R) belong to an important biological system that is involved in the regulation of normal growth, but that has also been recognized as playing a role in cancer. IGF-1R antagonists could be interesting for the testing of their potential antiproliferative properties as an alternative to IGF-1R tyrosine-kinase inhibitors or anti-IGF-1R monoclonal antibodies. In this study, we were inspired by the successful development of insulin dimers capable of antagonizing insulin effects on the insulin receptor (IR) by simultaneous binding to two separated binding sites and by blocking structural rearrangement of the IR. We designed and produced in Escherichia coli three different IGF-1 dimers in which IGF-1 monomers are interlinked through their N- and C-termini, with linkers having 8, 15 or 25 amino acids. We found that the recombinant products were susceptible to the formation of misfolded or reduced variants, but that some of them were able to bind IGF-1R in low nanomolar affinities and all of them activate IGF-1R proportionally to their binding affinities. Overall, our work can be considered as a pilot study that, although it did not lead to the discovery of new IGF-1R antagonists, explored the possibility of recombinant production of IGF-1 dimers and led to the preparation of active compounds. This work could inspire further studies dealing, for example, with the preparation of IGF-1 conjugates with specific proteins for the study of the hormone and its receptor or for therapeutic applications. The online version contains supplementary material available at 10.1007/s10989-023-10499-1.