Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease
Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease
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DOI：
10.1073/pnas.161274798
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发表时间：
2001-08-14
影响因子：
11.1
通讯作者：
Prusiner, SB
中科院分区：
文献类型：
--
作者：
Korth, C;May, BCH;Prusiner, SB
人类和动物的朊病毒疾病总是致命的。朊病毒由正常宿主朊蛋白（PrPC）的致病异构体（PrPSc）组成，并通过刺激PrPC转化为新生PrPSc进行复制。我们在这里报道，在慢性朊病毒感染的培养细胞中，吖啶和吩噻嗪的三环衍生物在有效浓度（EC50）在0.3和3mum之间时，对PrPSc形成的抑制作用达到了一半。氯丙嗪的EC50为3mum，而阿奎宁的EC50是其10倍。合成了多种以9取代吖啶为基础的喹吖啶类似物，它们表现出与氯丙嗪相似的抗朊病毒效力，并强调了侧链在介导抑制PrPSc形成中的重要性。因此，我们的研究表明，在中间环部分具有脂肪侧链的三环化合物构成了一类新的抗朊病毒试剂。由于阿奎宁和氯丙嗪已分别作为抗疟疾和抗精神病药物在人类中使用多年，并且已知可通过血脑屏障，因此我们认为它们是治疗克雅氏病和其他朊病毒疾病的直接候选药物。
Prion diseases in humans and animals are invariably fatal. Prions are composed of a disease-causing isoform (PrPSc) of the normal host prion protein (PrPC) and replicate by stimulating the conversion of PrPC into nascent PrPSc. We report here that tricyclic derivatives of acridine and phenothiazine exhibit half-maximal inhibition of PrPSc formation at effective concentrations (EC50) between 0.3 muM and 3 muM in cultured cells chronically infected with prions. The EC50 for chlorpromazine was 3 muM, whereas quinacrine was 10 times more potent. A variety of 9-substituted, acridine-based analogues of quinacrine were synthesized, which demonstrated variable antiprion potencies similar to those of chlorpromazine and emphasized the importance of the side chain in mediating the inhibition of PrPSc formation. Thus, our studies show that tricyclic compounds with an aliphatic side chain at the middle ring moiety constitute a new class of antiprion reagents. Because quinacrine and chlorpromazine have been used in humans for many years as antimalarial and antipsychotic drugs, respectively, and are known to pass the blood-brain barrier, we suggest that they are immediate candidates for the treatment of Creutzfeldt-Jakob disease and other prion diseases.