Structure‐based discovery of CZL80, a caspase‐1 inhibitor with therapeutic potential for febrile seizures and later enhanced epileptogenic susceptibility

Abstract

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 the caspase‐1 (Casp1) is involved in FS generation and potential to be a target for the treatment of FS is still unclear. Experimental Approach By using pharmacology and gene intervention methods, we tested the role of caspase‐1 in FS generation. Then, based on structural virtual screening against the active pocket of caspase‐1, we were aimed to find druggable and safe small‐molecular antagonists targeting caspase‐1 and test their therapeutic potential for FS. Key Results Here we show that caspase‐1 is essential for FS generation. The level of cleaved caspase‐1 increases 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. Based on structural virtual screening, over one million compounds against the active pocket of caspase‐1 were screened with molecular docking approaches. We yielded CZL80, a brain‐penetrable small molecule caspase‐1, which dramatically reduced neuronal excitability, incidence of FS generation, and relieved later enhanced epileptogenic susceptibility in adult. It was devoid of acute diazepam‐like respiratory depression and chronic liver toxicity. Conclusion and Implications These findings support that caspase‐1 is crucial for FS generation, and CZL80 serves as a promising small molecular inhibitor for FS and later enhanced epileptogenic susceptibility.