Breathing new life into West Nile virus therapeutics; discovery and study of zafirlukast as an NS2B-NS3 protease inhibitor
Breathing new life into West Nile virus therapeutics; discovery and study of zafirlukast as an NS2B-NS3 protease inhibitor
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DOI：
10.1016/j.ejmech.2018.08.077
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发表时间：
2018-09-05
影响因子：
6.7
通讯作者：
Salzameda, Nicholas T.
中科院分区：
文献类型：
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作者：
Martinez, Anastasia A.;Espinosa, Bianca A.;Salzameda, Nicholas T.
西尼罗河病毒（WNV）已蔓延到世界各地，导致神经侵入性疾病，没有可用的治疗方法。病毒NS 2B-NS 3蛋白酶对于WNV在宿主细胞中的存活和复制是必需的，并且是有希望的药物靶标。通过美国国立卫生研究院临床化合物库的酶筛选，我们报告了FDA批准的哮喘治疗药物扎鲁司特作为WNV NS 2B-NS 3蛋白酶抑制剂的发现。扎鲁司特被确定通过混合模式机制抑制蛋白酶，IC 50值为32 μ M。扎鲁司特的构效关系研究揭示了氨基甲酸环戊酯和N-芳基磺酰胺是NS 2B-NS 3蛋白酶抑制的关键结构元素。用苯基取代环戊基改善了抑制作用，导致IC 50为22 μ M。实验和计算对接分析支持扎鲁司特和类似物在NS 3蛋白上的变构位点结合的抑制模型，从而破坏NS 2B辅因子的结合，导致蛋白酶抑制。(C)2018 Elsevier Masson SAS。All rights reserved.
The West Nile virus (WNV) has spread throughout the world causing neuroinvasive diseases with no treatments available. The viral NS2B-NS3 protease is essential for WNV survival and replication in host cells and is a promising drug target. Through an enzymatic screen of the National Institute of Health clinical compound library, we report the discovery of zafirlukast, an FDA approved treatment for asthma, as an inhibitor for the WNV NS2B-NS3 protease. Zafirlukast was determined to inhibit the protease through a mixed mode mechanism with an IC50 value of 32 mu M. A structure activity relationship study of zafirlukast revealed the cyclopentyl carbamate and N-aryl sulfonamide as structural elements crucial for NS2B-NS3 protease inhibition. Replacing the cyclopentyl with a phenyl improved inhibition, resulting in an IC50 of 22 mu M. Experimental and computational docking analysis support the inhibition model of zafirlukast and analogs binding at an allosteric site on the NS3 protein, thereby disrupting the NS2B cofactor from binding, resulting in protease inhibition. (C) 2018 Elsevier Masson SAS. All rights reserved.