Translation Research Center for Protein Function Control, Department of Materials Science & Engineering, Yonsei University, Seoul, 120-749, Republic of Korea.
Biomaterials. 2010 Mar;31(8):2025-33. doi: 10.1016/j.biomaterials.2009.11.085.
Branched polyamines are effective in inhibiting prions in a cationic surface charge density dependent manner. However, toxicity associated with branched polyamines, in general, often hampers the successful application of the compounds to treat prion diseases. Here, we report that constitutively maintained cationic properties in branched polyamines reduced the intrinsic toxicity of the compounds while retaining the anti-prion activities. In prion-infected neuroblastoma cells, quaternization of amines in polyethyleneimine (PEI) and polyamidoamine (PAMAM) dendrimers markedly increased the nontoxic concentration ranges of the compounds and still supported, albeit reduced, an appreciable level of anti-prion activity in clearing prions from the infected cells. Furthermore, quaternized PEI was able to degrade prions at acidic pH conditions and inhibit the in vitro prion propagation facilitated by conversion of the normal prion protein isoform to its misfolded counterpart, although such activities were decreased by quaternization. Quaternized PAMAM was least effective in degrading prions but efficiently inhibited prion conversion with the same efficacy as unmodified PAMAM. Our results suggest that quaternization represents an effective strategy for developing nontoxic branched polyamines with potent anti-prion activity. This study highlights the importance of polyamine structural control for developing polyamine-based anti-prion agents and understanding of an action mechanism of quaternized branched polyamines.
支化多胺以阳离子表面电荷密度依赖的方式有效抑制朊病毒。然而，支化多胺通常与毒性相关，这常常阻碍了这些化合物成功应用于治疗朊病毒疾病。在这里，我们报告说，支化多胺中保持的阳离子性质降低了化合物的固有毒性，同时保留了抗朊病毒活性。在朊病毒感染的神经母细胞瘤细胞中，聚乙烯亚胺（PEI）和聚酰胺-胺（PAMAM）树枝状聚合物中胺的季铵化显著增加了化合物的无毒浓度范围，并且仍然支持，尽管降低了，从受感染细胞中清除朊病毒的可观水平的抗朊病毒活性。此外，季铵化的 PEI 能够在酸性 pH 条件下降解朊病毒，并抑制由正常朊病毒蛋白异构体转化为其错误折叠对应物而促进的体外朊病毒传播，尽管这种活性被季铵化降低。季铵化的 PAMAM 对降解朊病毒的效果最差，但能有效地抑制朊病毒转化，其效果与未修饰的 PAMAM 相同。我们的结果表明，季铵化是开发具有强大抗朊病毒活性的无毒支化多胺的有效策略。本研究强调了控制多胺结构对于开发基于多胺的抗朊病毒剂以及理解季铵化支化多胺的作用机制的重要性。
