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


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 (Ki) for the most potent 8-HQ inhibitor (compound 14) with an IC50 value of 2.01 ± 0.08 ?M using the tetra-peptide substrate was determined to be 5.8 ?M. This compound inhibits the WNV NS2B/NS3pro by a competitive mode of inhibition which is supported by molecular modeling.



West Nile Virus protease inhibitors, Molecular modeling and docking, competitive inhibitors of West Nile vrius protease, Structure activity relationship study among 8 hydroxyquinoline derivatives


Copyright 2012 Antiviral Research. This is a post-print version of a published paper that is available at: Recommended citation: Ezgimen, Manolya, Huiguo Lai, Niklaus H. Mueller, Kyungae Lee, Gregory Cuny, David A. Ostrov, and Radhakrishnan Padmanabhan. "Characterization of the 8-hydroxyquinoline scaffold for inhibitors of West Nile virus serine protease." Antiviral research 94, no. 1 (2012): 18-24. doi: 10.1016/j.antiviral.2012.02.003. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.