Transmissible spongiform encephalopathies (TSEs) are a group of lethal neurodegenerative diseases involving the structural conversion of cellular prion protein (PrP^C) into the pathogenic isoform (PrP^Sc) for which no effective treatment is currently available. Previous studies have implicated that a polymeric molecule with a repeating unit, such as pentosane polysulfate and polyamidoamide dendrimers, exhibits a potent anti-prion activity, suggesting that poly-(amino acid)s could be a candidate molecule for inhibiting prion propagation. Here, by screening a series of poly-(amino acid)s in a prion-infected neuroblastoma cell line (GT^FK), we identified poly-L-His as a novel anti-prion compound with an IC₅₀ value of 1.8 µg/mL (0.18 µM). This potent anti-prion activity was specific to a high-molecular-weight poly-L-His and absent in monomeric histidine or low-molecular-weight poly-L-His. Solution NMR data indicated that poly-L-His directly binds to the loop region connecting Helix 2 and Helix 3 of PrP^C and sterically blocks the structural conversion toward PrP^Sc. Poly-L-His, however, did not inhibit prion propagation in a prion-infected mouse when administered intraperitoneally, suggesting that the penetration of blood-brain barrier and/or the chemical stability of this polypeptide must be addressed before its application in vivo. Taken together, this study revealed the potential use of poly-L-His as a novel treatment against TSEs. (203 words)

传染性海绵状脑病（TSE）是一组致死性神经退行性疾病，涉及细胞病毒蛋白（PrP ^C）转变为病原体（PrP ^Sc）的结构，目前尚无有效的治疗方法。先前的研究暗示具有重复单元的聚合分子，例如戊烷多硫酸盐和聚酰胺酰胺树状大分子，表现出有效的抗-病毒活性，这表明聚氨基酸可能是抑制病毒传播的候选分子。在这里，通过在感染病毒的神经母细胞瘤细胞系（GT ^FK）中筛选一系列聚氨基酸，我们确定了聚L-His是具有IC ₅₀的新型抗-病毒化合物值为1.8 µg / mL（0.18 µM）。这种有效的抗-病毒活性对高分子量的聚-L-His具有特异性，而在单体组氨酸或低分子量的聚-L-His中则不存在。溶液NMR数据表明，聚-L-His直接结合到连接PrP ^C的螺旋2和螺旋3的环区域上，并在空间上阻断了向PrP ^Sc的结构转化。但是，当腹膜内给药时，聚-L-His不会抑制病毒感染的小鼠中ion病毒的繁殖，这表明在体内应用该多肽之前必须解决血脑屏障的渗透和/或化学稳定性。两者合计，这项研究揭示了聚L-His作为针对TSE的新型疗法的潜在用途。（203字）