ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
Department of Physics and Astronomy, Clemson University , Clemson, South Carolina 29634, United States.
Biomacromolecules. 2017 Dec 11;18(12):4249-4260. doi: 10.1021/acs.biomac.7b01301. Epub 2017 Oct 31.
Protein aggregation into amyloid fibrils is a ubiquitous phenomenon across the spectrum of neurodegenerative disorders and type 2 diabetes. A common strategy against amyloidogenesis is to minimize the populations of toxic oligomers and protofibrils by inhibiting protein aggregation with small molecules or nanoparticles. However, melanin synthesis in nature is realized by accelerated protein fibrillation to circumvent accumulation of toxic intermediates. Accordingly, we designed and demonstrated the use of star-shaped poly(2-hydroxyethyl acrylate) (PHEA) nanostructures for promoting aggregation while ameliorating the toxicity of human islet amyloid polypeptide (IAPP), the peptide involved in glycemic control and the pathology of type 2 diabetes. The binding of PHEA elevated the β-sheet content in IAPP aggregates while rendering a new morphology of "stelliform" amyloids originating from the polymers. Atomistic molecular dynamics simulations revealed that the PHEA arms served as rodlike scaffolds for IAPP binding and subsequently accelerated IAPP aggregation by increased local peptide concentration. The tertiary structure of the star nanoparticles was found to be essential for driving the specific interactions required to impel the accelerated IAPP aggregation. This study sheds new light on the structure-toxicity relationship of IAPP and points to the potential of exploiting star polymers as a new class of therapeutic agents against amyloidogenesis.
蛋白质聚集成淀粉样纤维是神经退行性疾病和 2 型糖尿病谱系中普遍存在的现象。一种常见的抗淀粉样变性策略是通过小分子或纳米颗粒抑制蛋白质聚集来最小化有毒寡聚体和原纤维的种群。然而，自然界中黑色素的合成是通过加速蛋白质的纤维化来实现的，以避免有毒中间体的积累。因此，我们设计并证明了使用星形聚（2-羟乙基丙烯酰胺）（PHEA）纳米结构来促进聚集，同时改善涉及血糖控制和 2 型糖尿病病理的人胰岛淀粉样多肽（IAPP）的毒性。PHEA 的结合提高了 IAPP 聚集体中的 β-折叠含量，同时形成了源自聚合物的新形态的“星状”淀粉样纤维。原子分子动力学模拟表明，PHEA 臂作为 IAPP 结合的棒状支架，通过增加局部肽浓度，从而加速 IAPP 的聚集。发现星形纳米颗粒的三级结构对于驱动推动加速 IAPP 聚集所需的特定相互作用至关重要。这项研究揭示了 IAPP 的结构-毒性关系，并指出了利用星形聚合物作为对抗淀粉样变性的一类新治疗剂的潜力。
