Semenyuk Pavel, Evstafyeva Diana, Izumrudov Vladimir, Muronetz Vladimir
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia.
Department of Chemistry, Lomonosov Moscow State University, 119234 Moscow, Russia.
Polymers (Basel). 2022 Apr 5;14(7):1478. doi: 10.3390/polym14071478.
Amyloid aggregation, including aggregation and propagation of prion protein, is a key factor in numerous human diseases, so-called amyloidosis, with a very poor ability for treatment or prevention. The present work describes the effect of sulfated or sulfonated polymers (sodium dextran sulfate, polystyrene sulfonate, polyanethole sulfonate, and polyvinyl sulfate) on different stages of amyloidogenic conversion and aggregation of the prion protein, which is associated with prionopathies in humans and animals. All tested polymers turned out to induce amyloid conversion of the ovine prion protein. As suggested from molecular dynamics simulations, this effect probably arises from destabilization of the native prion protein structure by the polymers. Short polymers enhanced its further aggregation, whereas addition of high-molecular poly(styrene sulfonate) inhibited amyloid fibrils formation. According to the seeding experiments, the protein-polymer complexes formed after incubation with poly(styrene sulfonate) exhibited significantly lower amyloidogenic capacity compared with the control fibrils of the free prion protein. The cytotoxicity of soluble oligomers was completely inhibited by treatment with poly(styrene sulfonate). To summarize, sulfonated polymers are a promising platform for the formulation of a new class of anti-prion and anti-amyloidosis therapeutics.
淀粉样蛋白聚集，包括朊病毒蛋白的聚集和传播，是众多人类疾病（即所谓的淀粉样变性）的关键因素，其治疗或预防能力非常差。目前的工作描述了硫酸化或磺化聚合物（硫酸葡聚糖钠、聚苯乙烯磺酸盐、聚茴芹磺酸盐和聚硫酸乙烯酯）对朊病毒蛋白淀粉样生成转化和聚集不同阶段的影响，朊病毒蛋白与人类和动物的朊病毒病有关。所有测试的聚合物都能诱导绵羊朊病毒蛋白的淀粉样转化。分子动力学模拟表明，这种效应可能源于聚合物使天然朊病毒蛋白结构不稳定。短聚合物促进其进一步聚集，而添加高分子量的聚苯乙烯磺酸盐则抑制淀粉样纤维的形成。根据种子实验，与游离朊病毒蛋白的对照纤维相比，与聚苯乙烯磺酸盐孵育后形成的蛋白质 - 聚合物复合物表现出明显较低的淀粉样生成能力。用聚苯乙烯磺酸盐处理可完全抑制可溶性寡聚体的细胞毒性。总之，磺化聚合物是开发新型抗朊病毒和抗淀粉样变性治疗药物的一个有前景的平台。
