Kumar Ammu Prasanna, Lee Sungmun, Lukman Suryani
Department of Chemistry, College of Arts and Sciences, Khalifa University, Abu Dhabi, United Arab Emirates.
Research Unit in Bioinformatics, Department of Biochemistry and Microbiology, Rhodes University, South Africa.
Curr Drug Targets. 2019;20(16):1680-1694. doi: 10.2174/1389450120666190719164316.
Amylin is a neuroendocrine peptide hormone secreted by pancreatic ß-cells; however, amylin is toxic to ß-cells when it is aggregated in type 2 diabetes mellitus (T2DM). It is important to understand amylin's structures and aggregation mechanism for the discovery and design of effective drugs to inhibit amylin aggregation. In this review, we investigated experimental and computational studies on amylin structures and inhibitors. Our review provides some novel insights into amylin, particularly for the design of its aggregation inhibitors to treat T2DM. We detailed the potential inhibitors that have been studied hitherto and highlighted the neglected need to consider different amylin attributes that depend on the presence/absence of physiologically relevant conditions, such as membranes. These conditions and the experimental methods can greatly influence the results of studies on amylininhibitor complexes. Text-mining over 3,000 amylin-related PubMed abstracts suggests the combined therapeutic potential of amylin with leptin and glucagon-like peptide-1, which are two key hormones in obesity. The results also suggest that targeting amylin aggregation can contribute to therapeutic efforts for Alzheimer's disease (AD). Therefore, we have also reviewed the role of amylin in other conditions including obesity and AD. Finally, we provided insights for designing inhibitors of different types (small molecules, proteins, peptides/mimetics, metal ions) to inhibit amylin aggregation.
胰淀素是一种由胰腺β细胞分泌的神经内分泌肽激素；然而，在2型糖尿病（T2DM）中，当胰淀素聚集时，它对β细胞具有毒性。了解胰淀素的结构和聚集机制对于发现和设计抑制胰淀素聚集的有效药物至关重要。在这篇综述中，我们研究了关于胰淀素结构和抑制剂的实验及计算研究。我们的综述为胰淀素提供了一些新的见解，特别是在设计其聚集抑制剂以治疗T2DM方面。我们详细介绍了迄今为止已研究的潜在抑制剂，并强调了忽视的需求，即需要考虑取决于生理相关条件（如膜）存在与否的不同胰淀素属性。这些条件和实验方法会极大地影响胰淀素 - 抑制剂复合物的研究结果。对3000多篇与胰淀素相关的PubMed摘要进行文本挖掘表明，胰淀素与瘦素和胰高血糖素样肽 - 1具有联合治疗潜力，而瘦素和胰高血糖素样肽 - 1是肥胖症中的两种关键激素。结果还表明，针对胰淀素聚集可有助于阿尔茨海默病（AD）的治疗。因此，我们还综述了胰淀素在包括肥胖症和AD在内的其他病症中的作用。最后，我们为设计不同类型（小分子、蛋白质、肽/模拟物、金属离子）的抑制剂以抑制胰淀素聚集提供了见解。
