A designer molecular chaperone against transmissible spongiform encephalopathy slows disease progression in mice and macaques
A designer molecular chaperone against transmissible spongiform encephalopathy slows disease progression in mice and macaques
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DOI：
10.1038/s41551-019-0349-8
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发表时间：
2019-03-01
影响因子：
28.1
通讯作者：
Kuwata, Kazuo
中科院分区：
文献类型：
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作者：
Yamaguchi, Keiichi;Kamatari, Yuji O.;Kuwata, Kazuo
传染性海绵状脑病 (TSE) 是一种致命的神经退行性疾病，缺乏治疗方案。在这里，我们发现通过对接模拟、分子动力学模拟和量子化学计算设计的分子伴侣（N,N'-([环己基亚甲基]二-4,1-亚苯基)双(2-[1-吡咯烷乙酰胺))）减缓了TSE的进展。在体外，设计分子伴侣可稳定正常细胞朊病毒蛋白，根除感染细胞中的朊病毒，防止耐药菌株的形成，并直接抑制朊病毒与异常聚集体之间的相互作用，如实时震动诱导转化和体外转化核磁共振所示。在感染朊病毒的小鼠中每周腹腔注射伴侣蛋白可延长其存活时间，在感染牛 TSE 的猕猴中每周静脉注射该化合物可减缓神经和心理症状的发展，并降低动物脑脊液中与疾病相关的生物标志物的浓度。伴侣化合物的从头合理设计可能会产生能够与不同朊病毒蛋白株结合以改善 TSE 病理学的疗法。
Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases that lack therapeutic solutions. Here, we show that the molecular chaperone (N,N'-([cyclohexylmethylene]di-4,1-phenylene)bis(2-[1-pyrrolidinynacetamide)), designed via docking simulations, molecular dynamics simulations and quantum chemical calculations, slows down the progress of TSEs. In vitro, the designer molecular chaperone stabilizes the normal cellular prion protein, eradicates prions in infected cells, prevents the formation of drug-resistant strains and directly inhibits the interaction between prions and abnormal aggregates, as shown via real-time quaking-induced conversion and in vitro conversion NMR. Weekly intraperitoneal injection of the chaperone in prion-infected mice prolonged their survival, and weekly intravenous administration of the compound in macaques infected with bovine TSE slowed down the development of neurological and psychological symptoms and reduced the concentration of disease-associated biomarkers in the animals' cerebrospinal fluid. The de novo rational design of chaperone compounds could lead to therapeutics that can bind to different prion protein strains to ameliorate the pathology of TSEs.