Structure-based discovery of CZL80, a caspase-1 inhibitor with therapeutic potential for febrile seizures and later enhanced epileptogenic susceptibility
Structure-based discovery of CZL80, a caspase-1 inhibitor with therapeutic potential for febrile seizures and later enhanced epileptogenic susceptibility
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基于结构的 CZL80 发现，这是一种 caspase-1 抑制剂，具有治疗热性惊厥和随后增强癫痫易感性的潜力
DOI：
10.1111/bph.15076
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发表时间：
2020-06-01
影响因子：
7.3
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
--
作者：
Tang, Yangshun;Feng, Bo;Chen, Zhong
背景与目的热性惊厥（FS）是儿童期最常见的惊厥，常伴随癫痫发生，但控制不佳。炎症过程与癫痫的病理生理有关。然而，caspase-1是否参与FS的产生以及是否可能成为FS的治疗靶点尚不清楚。实验方法采用药物和基因干预的方法对C57BL/6J小鼠进行实验，评估caspase-1在FS发生中的作用。我们采用针对caspase-1活性位点的结构虚拟筛选，在体外筛选可药物和安全的caspase-1低分子量抑制剂的化合物。其中一种化合物通过新生小鼠的FS模型和成年小鼠的癫痫发生模型在体内测试其治疗潜力。在小鼠中，劈裂caspase-1水平在FS发病前升高。Caspase-1（-/-）小鼠对FS有抗性，且神经元兴奋性低于野生型小鼠。相反，在子宫电穿孔中过度表达caspase-1会增加神经元的兴奋性和对FS的易感性。结构虚拟筛选，使用分子对接方法对超过100万种化合物的caspase-1活性位点进行筛选，得到了CZL80，一种可穿透脑的低分子量caspase-1抑制剂。在新生小鼠中，CZL80显著降低了神经元兴奋性和FS产生的发生率，并且在成年小鼠中，缓解了后来增强的癫痫易感性。CZL80无急性地西泮样呼吸抑制和慢性肝毒性。结论和意义Caspase-1对FS的产生至关重要。CZL80是一种很有前途的低分子量FS抑制剂，可增强癫痫易感性。
Background and Purpose Febrile seizures (FS), the most common seizures in childhood and often accompanied by later epileptogenesis, are not well controlled. Inflammatory processes have been implicated in the pathophysiology of epilepsy. However, whether caspase-1 is involved in FS generation and could be a target for the treatment of FS is still unclear.Experimental Approach By using pharmacological and gene intervention methods in C57BL/6J mice, we assessed the role of caspase-1 in FS generation. We used structural virtual screening against the active site of caspase-1, to screen compounds for druggable and safe low MW inhibitors of caspase-1 in vitro. One compound was chosen to test in vivo for therapeutic potential, using FS models in neonatal mice and epileptogenesis in adult mice.Key Results In mice, levels of cleaved caspase-1 increased prior to FS onset. Caspase-1(-/-) mice were resistant to FS and showed lower neuronal excitability than wild-type littermates. Conversely, overexpression of caspase-1 using in utero electroporation increased neuronal excitability and enhanced susceptibility to FS. The structural virtual screening, using molecular docking approaches for the active site of caspase-1 of over 1 million compounds yielded CZL80, a brain-penetrable, low MW inhibitor of caspase-1. In neonatal mice, CZL80 markedly reduced neuronal excitability and incidence of FS generation, and, in adult mice, relieved later enhanced epileptogenic susceptibility. CZL80 was devoid of acute diazepam-like respiratory depression and chronic liver toxicity.Conclusion and Implications Caspase-1 is essential for FS generation. CZL80 is a promising low MW inhibitor of FS and later enhanced epileptogenic susceptibility.