Quinoline derivatives are therapeutic candidates for transmissible spongiform encephalopathies
Quinoline derivatives are therapeutic candidates for transmissible spongiform encephalopathies
复制标题
DOI：
10.1128/jvi.78.3.1281-1288.2004
复制
发表时间：
2004-02-01
影响因子：
5.4
通讯作者：
Iwaki, T
中科院分区：
文献类型：
--
作者：
Murakami-Kubo, I;Doh-ura, K;Iwaki, T
我们以前报道，奎纳克林抑制形成异常朊蛋白（PrPres），在传染性海绵状脑病，或朊病毒病的发病机制中的关键分子，在羊瘙痒症感染的神经母细胞瘤细胞。为了阐明其抑制作用的结构方面，在本研究中筛选了具有喹啉环的各种化学品。对羊瘙痒病感染的神经母细胞瘤细胞的分析表明，侧链在喹啉环的4位含有奎宁环的化学物质（以奎宁为代表）在10（-1）至10（1）μ M的50%抑制剂量范围内抑制PrPres的形成。另一方面，在喹啉环的2位上具有侧链的化学品（由2，2 '-联喹啉表示）在10（-3）至10（-1）μ M范围内的50%抑制剂量下更有效地抑制PrPres的形成。代谢标记的研究表明，奎宁或联喹啉的行动是不是由于正常朊病毒蛋白的生物合成或营业额的任何改变，而表面等离子体共振分析表明，强结合亲和力的联喹啉与重组朊病毒蛋白。体内研究表明，脑室内灌注奎宁或联喹啉4周可有效延长实验性小鼠脑内感染模型的潜伏期。研究结果表明，喹啉衍生物与含氮的侧链有可能既抑制PrPres的形成在体外，并延长感染动物的潜伏期。这些化学品是用于治疗传染性海绵状脑病的治疗药物的新候选物。
We previously reported that quinacrine inhibited the formation of an abnormal prion protein (PrPres), a key molecule in the pathogenesis of transmissible spongiform encephalopathy, or prion disease, in scrapie-infected neuroblastoma cells. To elucidate the structural aspects of its inhibiting action, various chemicals with a quinoline ring were screened in the present study. Assays of the scrapie-infected neuroblastoma cells revealed that chemicals with a side chain containing a quinuclidine ring at the 4 position of a quinoline ring (represented by quinine) inhibited the PrPres formation at a 50% inhibitory dose ranging from 10(-1) to 10(1) muM. On the other hand, chemicals with a side chain at the 2 position of a quinoline ring (represented by 2,2'-biquinoline) more effectively inhibited the PrPres formation at a 50% inhibitory dose ranging from 10(-3) to 10(-1) muM. A metabolic labeling study revealed that the action of quinine or biquinoline was not due to any alteration in the biosynthesis or turnover of normal prion protein, whereas surface plasmon resonance analysis showed a strong binding affinity of biquinoline with a recombinant prion protein. In vivo studies revealed that 4-week intraventricular infusion of quinine or biquinoline was effective in prolonging the incubation period in experimental mouse models of intracerebral infection. The findings suggest that quinoline derivatives with a nitrogen-containing side chain have the potential of both inhibiting PrPres formation in vitro and prolonging the incubation period of infected animals. These chemicals are new candidates for therapeutic drugs for use in the treatment of transmissible spongiform encephalopathies.