Promising antiviral protease inhibitors With no vaccine or proven effective drug against the virus that causes coronavirus disease 2019 (COVID-19), scientists are racing to find clinical antiviral treatments. A promising drug target is the viral main protease Mpro, which plays a key role in viral replication and transcription. Dai et al. designed two inhibitors, 11a and 11b, based on analyzing the structure of the Mpro active site. Both strongly inhibited the activity of Mpro and showed good antiviral activity in cell culture. Compound 11a had better pharmacokinetic properties and low toxicity when tested in mice and dogs, suggesting that this compound is a promising drug candidate. Science, this issue p. 1331 Two peptidomimetic aldehydes were designed, synthesized, and evaluated as antiviral drug candidates. SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.

中文翻译：

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针对 SARS-CoV-2 主蛋白酶的抗病毒候选药物的基于结构的设计

有前景的抗病毒蛋白酶抑制剂由于没有疫苗或经证实有效的药物可以对抗导致 2019 年冠状病毒病 (COVID-19) 的病毒，科学家们正在竞相寻找临床抗病毒治疗方法。一个有前景的药物靶点是病毒主蛋白酶 Mpro，它在病毒复制和转录中起关键作用。戴等人。基于分析 Mpro 活性位点的结构，设计了两种抑制剂 11a 和 11b。两者均强烈抑制 Mpro 的活性，并在细胞培养中显示出良好的抗病毒活性。当在小鼠和狗中进行测试时，化合物 11a 具有更好的药代动力学特性和低毒性，表明该化合物是一种有前途的候选药物。科学，这个问题 p。1331 设计、合成和评估了两种拟肽醛作为抗病毒药物候选物。SARS-CoV-2（严重急性呼吸系统综合症冠状病毒 2）是导致全球 COVID-19（冠状病毒病 2019）爆发的病原体。SARS-CoV-2的主要蛋白酶Mpro是一种关键酶，在介导病毒复制和转录中起关键作用。我们设计并合成了两种针对 Mpro 的先导化合物（11a 和 11b）。两者都表现出优异的抑制活性和有效的抗 SARS-CoV-2 感染活性。SARS-CoV-2 Mpro 与 11a 或 11b 复合物的 X 射线晶体结构（均以 1.5 埃的分辨率确定）表明，11a 和 11b 的醛基与 Mpro 的半胱氨酸 145 共价结合。两种化合物都显示出良好的体内药代动力学特性，11a 还表现出低毒性，这表明这些化合物是有希望的候选药物。