Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States.
Department of Molecular Virology and Microbiology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States.
J Med Chem. 2021 Mar 11;64(5):2777-2800. doi: 10.1021/acs.jmedchem.0c02070. Epub 2021 Feb 17.
Flaviviruses, including Zika, dengue, and West Nile viruses, are important human pathogens. The highly conserved NS2B-NS3 protease of Flavivirus is essential for viral replication and therefore a promising drug target. Through compound screening, followed by medicinal chemistry studies, a novel series of 2,5,6-trisubstituted pyrazine compounds are found to be potent, allosteric inhibitors of Zika virus protease (ZVpro) with IC values as low as 130 nM. Their structure-activity relationships are discussed. The ZVpro inhibitors also inhibit homologous proteases of dengue and West Nile viruses, and their inhibitory activities are correlated. The most potent compounds and potently inhibited Zika virus replication in cells with EC values of 300-600 nM and in a mouse model of Zika infection. These compounds represent novel pharmacological leads for drug development against Flavivirus infections.
黄病毒属，包括寨卡病毒、登革热病毒和西尼罗河病毒，是重要的人类病原体。黄病毒高度保守的 NS2B-NS3 蛋白酶对于病毒复制至关重要，因此是一个有前途的药物靶点。通过化合物筛选，然后进行药物化学研究，发现了一系列新型的 2,5,6-三取代吡嗪化合物，它们是有效的 Zika 病毒蛋白酶（ZVpro）的别构抑制剂，IC 值低至 130 nM。讨论了它们的构效关系。ZVpro 抑制剂还抑制登革热和西尼罗河病毒的同源蛋白酶，它们的抑制活性相关。最有效的化合物 和 在细胞中强烈抑制寨卡病毒复制，EC 值为 300-600 nM，并在寨卡病毒感染的小鼠模型中。这些化合物代表了针对黄病毒感染的药物开发的新型药理学先导化合物。
