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Mechanism study on the abnormal accumulation and deposition of islet amyloid polypeptide by cold-spray ionization mass spectrometry
Analyst ( IF 4.2 ) Pub Date : 2020-08-20 , DOI: 10.1039/d0an01034k
Su Chen 1, 2, 3, 4, 5 , Yang Liu 5, 6, 7 , Yanan Zhou 5, 6, 7 , Lan He 5, 6, 7 , Jin Ouyang 1, 2, 3, 4, 5
Affiliation  

The abnormal accumulation and deposition of islet amyloid polypeptide (IAPP) are important causes of type-2 diabetes mellitus (T2DM). The common anti-amyloid strategy employs inhibitors to prevent the formation of oligomers and the cytotoxicity caused by them, thus reducing the production of amyloid fibres. Therefore, the real characterization of the oligomers formed at the early stage of aggregation is crucial to understanding the structure of IAPP and the drug development of T2DM. For the first time, in this study, native cold-spray ionization mass spectrometry (CSI-MS) technology was employed to characterize the oligomers. It was found that CSI was more suitable for the determination of these unstable species compared to traditional ESI-MS. The ionic strengths, organic solvent and pH all had effects on the characterization of oligomers and the stability of protein conformation. The MS/MS experiments showed that odd-charge dimer ions were mainly composed of two monomer products. Moreover, a CSI-MS method for the rapid screening of IAPP–inhibitors was established and two of the most potential inhibitors (rutin and quercitrin) were screened from a series of flavonoids. Then, the structure–activity relationship and the mechanism between flavonoids and IAPP were studied. The results showed that 3-OH and sugar chains play a vital role and hydrogen bonds are the main binding force. We further confirmed that rutin and quercitrin could effectively inhibit the fibre formation of IAPP by fluorescence and TEM experiments. This study provides a new insight for analyzing the structure of IAPP and screening potential drugs for T2DM.

中文翻译:

冷喷雾电离质谱法研究胰岛淀粉样多肽异常积累和沉积的机理

胰岛淀粉样多肽(IAPP)的异常积累和沉积是2型糖尿病(T2DM)的重要原因。常见的抗淀粉样蛋白策略采用抑制剂来防止寡聚物的形成和由其引起的细胞毒性,从而减少淀粉样蛋白纤维的产生。因此,在聚集初期形成的低聚物的真实表征对于了解IAPP的结构和T2DM的药物开发至关重要。在本研究中,首次使用天然冷喷雾电离质谱(CSI-MS)技术来表征低聚物。发现与传统的ESI-MS相比,CSI更适合于确定这些不稳定的物种。离子强度 有机溶剂和pH均对低聚物的表征和蛋白质构象的稳定性有影响。MS / MS实验表明,奇电荷二聚体离子主要由两种单体产物组成。此外,建立了用于快速筛选IAPP抑制剂的CSI-MS方法,并从一系列类黄酮中筛选出了两种最有潜力的抑制剂(芦丁和槲皮苷)。然后,研究了类黄酮与IAPP之间的构效关系及其机理。结果表明3-OH和糖链起着至关重要的作用,氢键是主要的结合力。通过荧光和TEM实验,我们进一步证实了芦丁和槲皮素可以有效抑制IAPP的纤维形成。
更新日期:2020-09-08
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