Mol Pharm. 2020 Jun 1;17(6):1827-1834. doi: 10.1021/acs.molpharmaceut.9b01080. Epub 2020 May 12.
Amyloidosis is a well-known but poorly understood phenomenon caused by the aggregation of proteins, often leading to pathological conditions. For example, the aggregation of insulin poses significant challenges during the preparation of pharmaceutical insulin formulations commonly used to treat diabetic patients. Therefore, it is essential to develop inhibitors of insulin aggregation for potential biomedical applications and for important mechanistic insights into amyloidogenic pathways. Here, we have identified a small molecule M1, which causes a dose-dependent reduction in insulin fibril formation. Biophysical analyses and docking results suggest that M1 likely binds to partially unfolded insulin intermediates. Further, M1-treated insulin had lower cytotoxicity and remained functionally active in regulating cell proliferation in cultured wing epithelium. Thus, M1 is of great interest as a novel agent for inhibiting insulin aggregation during biopharmaceutical manufacturing.
淀粉样变是一种众所周知但知之甚少的现象，由蛋白质聚集引起，常导致病理状况。例如，胰岛素的聚集在制备常用于治疗糖尿病患者的药用胰岛素制剂时带来了重大挑战。因此，开发胰岛素聚集抑制剂对于潜在的生物医学应用和对淀粉样变途径的重要机制见解至关重要。在这里，我们已经确定了一种小分子 M1，它可导致胰岛素纤维形成的剂量依赖性减少。生物物理分析和对接结果表明，M1 可能与部分展开的胰岛素中间产物结合。此外，用 M1 处理的胰岛素的细胞毒性更低，并且在培养的 wing 上皮细胞中仍然具有调节细胞增殖的功能活性。因此，M1 作为一种在生物制药制造过程中抑制胰岛素聚集的新型试剂具有很大的研究价值。
