Pharmacological Agents Targeting the Cellular Prion Protein.
Pharmacological Agents Targeting the Cellular Prion Protein.
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DOI：
10.3390/pathogens7010027
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发表时间：
2018-03-07
期刊：
影响因子：
--
通讯作者：
Biasini E
中科院分区：
文献类型：
--
作者：
Barreca ML;Iraci N;Biggi S;Cecchetti V;Biasini E
朊病毒疾病与细胞朊病毒蛋白（PrPC）（一种在多种细胞类型表面表达的糖蛋白）转化为错误折叠的构象异构体（PrP 或 PrPSc 的痒病形式）有关，并在受影响个体的脑组织中积聚。 PrPSc 是一种自催化蛋白质组装体，能够招募 PrPC 的天然构象异构体，并导致它们重排成新的 PrPSc 分子。之前的几次尝试鉴定针对朊病毒疾病的治疗剂都以 PrPSc 为目标，并且许多化合物在实验模型中显示出有效的抗朊病毒作用。不幸的是，到目前为止，这些分子都没有成功转化为朊病毒疾病的有效疗法。此外，越来越多的证据表明，PrPSc 可能是一个困难的药理学靶点，因为其结构不明确、组成异质，并且能够产生不同的结构构象异构体（称为朊病毒株），从而逃避药理学干预。在过去的十年中，出现了一种不太直观的策略来克服所有这些问题：针对 PrPC，任何朊病毒株复制的常见底物。这种替代方法具有多种技术和理论优势，包括为其他神经退行性疾病提供治疗效果的可能性，基于最近的观察表明 PrPC 在传递不同错误折叠蛋白的神经毒性信号中的作用。在这里，我们概述了声称通过直接结合 PrPC 发挥抗朊病毒作用的化合物，讨论了每种化学类别的药理学特性和治疗潜力。
Prion diseases are associated with the conversion of the cellular prion protein (PrPC), a glycoprotein expressed at the surface of a wide variety of cell types, into a misfolded conformer (the scrapie form of PrP, or PrPSc) that accumulates in brain tissues of affected individuals. PrPSc is a self-catalytic protein assembly capable of recruiting native conformers of PrPC, and causing their rearrangement into new PrPSc molecules. Several previous attempts to identify therapeutic agents against prion diseases have targeted PrPSc, and a number of compounds have shown potent anti-prion effects in experimental models. Unfortunately, so far, none of these molecules has successfully been translated into effective therapies for prion diseases. Moreover, mounting evidence suggests that PrPSc might be a difficult pharmacological target because of its poorly defined structure, heterogeneous composition, and ability to generate different structural conformers (known as prion strains) that can elude pharmacological intervention. In the last decade, a less intuitive strategy to overcome all these problems has emerged: targeting PrPC, the common substrate of any prion strain replication. This alternative approach possesses several technical and theoretical advantages, including the possibility of providing therapeutic effects also for other neurodegenerative disorders, based on recent observations indicating a role for PrPC in delivering neurotoxic signals of different misfolded proteins. Here, we provide an overview of compounds claimed to exert anti-prion effects by directly binding to PrPC, discussing pharmacological properties and therapeutic potentials of each chemical class.
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