Beyond Basicity: Discovery of Nonbasic DENV-2 Protease Inhibitors with Potent Activity in Cell Culture

Kuehl Nikos; Leuthold Mila M.; Behnam Mira A. M.; Klein Christian D.

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Beyond Basicity: Discovery of Nonbasic DENV-2 Protease Inhibitors with Potent Activity in Cell Culture

机译：超越碱性：发现具有细胞培养中有效活性的非比基因DenV-2蛋白酶抑制剂

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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.

机译：病毒丝氨酸蛋白酶NS2B-NS3是抗登革热病毒和其他黄病毒药物发现的有希望的靶点之一。蛋白酶的分子识别偏好偏好碱性带正电部分作为底物和抑制剂，这导致药代动力学负债和与宿主蛋白酶（如凝血酶）的脱靶相互作用。我们在此介绍了专门针对发现和开发黄病毒蛋白酶的非荷电小分子抑制剂的研究结果。发现这些化合物的一个关键因素是登革热蛋白酶DENV2proHeLa系统的细胞报告基因分析。广泛的结构-活性关系探索导致新型苯甲酰胺衍生物在病毒复制试验中具有亚微摩尔活性（EC50 0.24μM），对脱靶蛋白酶具有选择性，且细胞毒性可忽略不计。与之前发表的大多数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的相似性，并包括有希望进一步临床前开发的候选药物。

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《Journal of Medicinal Chemistry》 |2021年第8期|共21页
作者
Kuehl Nikos; Leuthold Mila M.; Behnam Mira A. M.; Klein Christian D.;
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Heidelberg Univ Inst Pharm &

Mol Biotechnol IPMB Med Chem D-69120 Heidelberg Germany;

Heidelberg Univ Inst Pharm &

Mol Biotechnol IPMB Med Chem D-69120 Heidelberg Germany;

Heidelberg Univ Inst Pharm &

Mol Biotechnol IPMB Med Chem D-69120 Heidelberg Germany;

Heidelberg Univ Inst Pharm &

Mol Biotechnol IPMB Med Chem D-69120 Heidelberg Germany;

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正文语种 eng
中图分类药学;
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Beyond Basicity: Discovery of Nonbasic DENV-2 Protease Inhibitors with Potent Activity in Cell Culture

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