Structure-based drug design identifies polythiophenes as antiprion compounds
Structure-based drug design identifies polythiophenes as antiprion compounds
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DOI：
10.1126/scitranslmed.aab1923
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发表时间：
2015-08-05
影响因子：
17.1
通讯作者：
Aguzzi, Adriano
中科院分区：
文献类型：
--
作者：
Herrmann, Uli S.;Schuetz, Anne K.;Aguzzi, Adriano
朊病毒引起传染性海绵状脑病，目前尚无治疗方法。朊病毒由PrPSc组成，PrPSc是细胞朊病毒蛋白（PrPC）的错误折叠和聚集形式。我们探讨了发光共轭聚噻吩（LCPs）的抗朊病毒特性的绑定和稳定有序的蛋白质聚集体。通过给朊病毒感染小鼠的大脑通过渗透微泵的结构不同的LCP库，我们发现，抗朊病毒活性需要至少五个噻吩环轴承定期间隔羧基侧基。固态核磁共振分析和分子动力学模拟表明，阴离子侧链相互作用的互补，定期间隔的阳离子淀粉样蛋白模型朊病毒残基。这些发现使我们能够提取控制LCP和蛋白质聚集体之间相互作用的结构规则，然后我们使用这些规则来设计一组具有优化结合的新LCP。新的一组LCP在朊病毒感染的小鼠中显示出强大的预防和治疗效力，其中先导化合物将存活期延长>80%，并显示出对小鼠和仓鼠朊病毒的活性以及腹膜内给药至小鼠后的功效。这些结果证明了可用于治疗异常蛋白质聚集疾病如朊病毒疾病的化合物的靶向化学设计的可行性。
Prions cause transmissible spongiform encephalopathies for which no treatment exists. Prions consist of PrPSc, a misfolded and aggregated form of the cellular prion protein (PrPC). We explore the antiprion properties of luminescent conjugated polythiophenes (LCPs) that bind and stabilize ordered protein aggregates. By administering a library of structurally diverse LCPs to the brains of prion-infected mice via osmotic minipumps, we found that antiprion activity required a minimum of five thiophene rings bearing regularly spaced carboxyl side groups. Solid-state nuclear magnetic resonance analyses and molecular dynamics simulations revealed that anionic side chains interacted with complementary, regularly spaced cationic amyloid residues of model prions. These findings allowed us to extract structural rules governing the interaction between LCPs and protein aggregates, which we then used to design a new set of LCPs with optimized binding. The new set of LCPs showed robust prophylactic and therapeutic potency in prion-infected mice, with the lead compound extending survival by >80% and showing activity against both mouse and hamster prions as well as efficacy upon intraperitoneal administration into mice. These results demonstrate the feasibility of targeted chemical design of compounds that may be useful for treating diseases of aberrant protein aggregation such as prion disease.