Chikungunya virus (CHIKV) is responsible for the most endemic alphavirus infections called Chikungunya. The endemicity of Chikungunya has increased over the past two decades, and it is a pathogen with pandemic potential. There is currently no approved direct-acting antiviral to treat the disease. As part of our antiviral drug discovery program focused on alphaviruses and the non-structural protein 2 protease, we discovered that and can inhibit CHIKV nsP2 protease and block the replication of CHIKV in cell cultures. Both compounds are metabolically stable to human liver microsomal and S9 enzymes. has excellent oral bioavailability in pharmacokinetics studies in mice and ameliorated Chikungunya symptoms in preliminary efficacy studies in mice. exhibited an excellent safety profile in safety pharmacology and off-target screening assays, making and its analogs good candidates for drug development against Chikungunya.

中文翻译：

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非结构蛋白 2 蛋白酶抑制剂在基孔肯雅热小鼠模型中显示出良好的功效


基孔肯雅病毒 (CHIKV) 导致最流行的甲病毒感染，称为基孔肯雅病毒。过去二十年来，基孔肯雅热的流行有所增加，它是一种具有大流行潜力的病原体。目前还没有批准的直接作用抗病毒药物来治疗这种疾病。作为我们专注于甲病毒和非结构蛋白 2 蛋白酶的抗病毒药物发现计划的一部分，我们发现它可以抑制 CHIKV nsP2 蛋白酶并阻止 CHIKV 在细胞培养物中的复制。这两种化合物对人肝微粒体和 S9 酶均具有代谢稳定性。在小鼠药代动力学研究中具有优异的口服生物利用度，并在小鼠初步疗效研究中改善基孔肯雅热症状。在安全药理学和脱靶筛选试验中表现出优异的安全性，使其及其类似物成为针对基孔肯雅热药物开发的良好候选者。