Beyond Basicity: Discovery of Nonbasic DENV-2 Protease Inhibitors with Potent Activity in Cell Culture
Beyond Basicity: Discovery of Nonbasic DENV-2 Protease Inhibitors with Potent Activity in Cell Culture
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DOI：
10.1021/acs.jmedchem.0c02042
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发表时间：
2021-04-14
影响因子：
7.3
通讯作者：
Klein, Christian D.
中科院分区：
文献类型：
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作者：
Kuehl, Nikos;Leuthold, Mila M.;Klein, Christian D.
病毒丝氨酸蛋白酶NS 2B-NS 3是发现抗登革病毒和其他黄病毒药物的有前景的靶标之一。蛋白酶的分子识别偏好有利于碱性带正电荷的部分作为底物和抑制剂，这导致与宿主蛋白酶如凝血酶的药代动力学责任和脱靶相互作用。我们在这里提出的努力，专门针对发现和开发的不带电的，小分子抑制剂的黄病毒蛋白酶的结果。发现这些化合物的关键因素是登革热蛋白酶的细胞报告基因测定，DENV 2 proHeLa系统。广泛的结构-活性关系的探索导致在新的苯甲酰胺衍生物与亚微摩尔的活动，在病毒复制试验（EC 50 0.24 μ M），对脱靶蛋白酶的选择性，和可忽略不计的细胞毒性。与大多数先前发表的活性位点导向的黄病毒蛋白酶抑制剂相比，这种结构类别增加了药物相似性，并包括有前途的候选物用于进一步的临床前开发。
The viral serine protease NS2B-NS3 is one of the promising targets for drug discovery against dengue virus and other flaviviruses. The molecular recognition preferences of the protease favor basic, positively charged moieties as substrates and inhibitors, which leads to pharmacokinetic liabilities and off-target interactions with host proteases such as thrombin. We here present the results of efforts that were aimed specifically at the discovery and development of noncharged, small-molecular inhibitors of the flaviviral proteases. A key factor in the discovery of these compounds was a cellular reporter gene assay for the dengue protease, the DENV2proHeLa system. Extensive structure-activity relationship explorations resulted in novel benzamide derivatives with submicromolar activities in viral replication assays (EC50 0.24 mu M), selectivity against off-target proteases, and negligible cytotoxicity. This structural class has increased drug-likeness compared to most of the previously published active-site-directed flaviviral protease inhibitors and includes promising candidates for further preclinical development.