Quinacrine promotes replication and conformational mutation of chronic wasting disease prions
Quinacrine promotes replication and conformational mutation of chronic wasting disease prions
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DOI：
10.1073/pnas.1322377111
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发表时间：
2014-04-22
影响因子：
11.1
通讯作者：
Telling, Glenn C.
中科院分区：
文献类型：
--
作者：
Bian, Jifeng;Kang, Hae-Eun;Telling, Glenn C.
奎纳克林能够降低感染实验适应性朊病毒的小鼠细胞中致病性朊蛋白（PrPSc）的水平，导致了几项针对朊病毒疾病患者的临床研究失败，这是一项为期10年的投资，旨在了解其作用机制，并生产预期具有更大疗效的相关化合物。我们在这里显示，在这一报道的抑制作用形成鲜明对比，奎纳克林增强鹿和麋鹿PrPSc的积累，并促进朊病毒的传播，导致慢性消耗性疾病（CWD），一种致命的，可传播的，神经退行性疾病的鹿科动物的不确定的人畜共患病的潜力。令人惊讶的是，尽管奎纳克林处理的细胞中朊病毒滴度增加，但由此产生的朊病毒的传播延长了孵育时间，并改变了患病转基因小鼠大脑中PrPSc的沉积模式。这一意外结果与奎纳克林影响慢性消耗病朊病毒的内在特性一致。因此，奎纳克林处理的慢性消耗病朊病毒由改变的PrPSc构象组成。我们的研究结果为药物诱导的朊病毒构象突变提供了令人信服的证据，而不需要产生原始菌株的耐药变体。更具体地说，他们表明，一种能够在一个物种/菌株环境中抑制朊病毒并因此用于治疗人类朊病毒疾病的药物，改善了另一种物种/菌株环境中的复制能力，因此迫使重新考虑目前筛选抗朊病毒化合物的策略。
Quinacrine's ability to reduce levels of pathogenic prion protein (PrPSc) in mouse cells infected with experimentally adapted prions led to several unsuccessful clinical studies in patients with prion diseases, a 10-y investment to understand its mechanism of action, and the production of related compounds with expectations of greater efficacy. We show here, in stark contrast to this reported inhibitory effect, that quinacrine enhances deer and elk PrPSc accumulation and promotes propagation of prions causing chronic wasting disease (CWD), a fatal, transmissible, neurodegenerative disorder of cervids of uncertain zoonotic potential. Surprisingly, despite increased prion titers in quinacrine-treated cells, transmission of the resulting prions produced prolonged incubation times and altered PrPSc deposition patterns in the brains of diseased transgenic mice. This unexpected outcome is consistent with quinacrine affecting the intrinsic properties of the CWD prion. Accordingly, quinacrine-treated CWD prions were comprised of an altered PrPSc conformation. Our findings provide convincing evidence for drug-induced conformational mutation of prions without the prerequisite of generating drug-resistant variants of the original strain. More specifically, they show that a drug capable of restraining prions in one species/strain setting, and consequently used to treat human prion diseases, improves replicative ability in another and therefore force reconsideration of current strategies to screen antiprion compounds.