Characterization of the 8-hydroxyquinoline scaffold for inhibitors of West Nile virus serine protease

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• 作者：Manolya Ezgimen^a ; ¹ ; Huiguo Lai^a ; ¹ ; Niklaus H. Mueller^a ; ² ; Kyungae Lee^b ; Gregory Cuny^b ; ^c ; David A. Ostrov^d ; Radhakrishnan Padmanabhan^a ; ^{rp55@georgetown.edu}
• 关键词：West Nile virus protease inhibitors ; Molecular modeling and docking ; Competitive inhibitors of West Nile virus protease ; Structure activity relationship study among 8-hydroxyquinoline derivatives
• 刊名：Antiviral Research
• 出版年：2012
• 期刊代码：7_01663542
• 类别：imm
• 出版时间：April, 2012
• 卷：94
• 期：1
• 页码：18-24
• 文件大小：621 K

摘要

West Nile virus (WNV) is a mosquito-borne member of flaviviruses that causes significant morbidity and mortality especially among children. There is currently no approved vaccine or antiviral therapeutic for human use. In a previous study, we described compounds containing the 8-hydroxyquinoline (8-HQ) scaffold as inhibitors of WNV serine protease (NS2B/NS3pro) in a high throughput screen (HTS) using the purified WNV NS2B/NS3pro as the target. In this study, we analyzed potencies of some commercially available as well as chemically synthesized derivatives of 8-HQ by biochemical assays. An insight into the contribution of various substitutions of 8-HQ moiety for inhibition of the protease activity was revealed. Most importantly, the substitution of the N1 of the 8-HQ ring by -CH- in compound 26 significantly reduced the inhibition of the viral protease by this naphthalen-1-ol derivative. The kinetic constant (K_i) for the most potent 8-HQ inhibitor (compound 14) with an IC₅₀ value of 2.01 卤 0.08 渭M using the tetra-peptide substrate was determined to be 5.8 渭M. This compound inhibits the WNV NS2B/NS3pro by a competitive mode of inhibition which is supported by molecular modeling.