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

dc.contributor.authorEzgimen, Manolya
dc.contributor.authorLai, Huiguo
dc.contributor.authorMueller, Niklaus H.
dc.contributor.authorLee, Kyungae
dc.contributor.authorCuny, Gregory D.
dc.contributor.authorOstrov, David A.
dc.contributor.authorPadmanabhan, Radhakrishnan
dc.date.accessioned2020-03-10T17:31:23Z
dc.date.available2020-03-10T17:31:23Z
dc.date.issued2013-04
dc.description.abstractWest 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.
dc.identifier.citationCopyright 2012 Antiviral Research. This is a post-print version of a published paper that is available at: https://www.sciencedirect.com/science/article/pii/S0166354212000368. 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.
dc.identifier.urihttps://hdl.handle.net/10657/5951
dc.language.isoen_US
dc.publisherAntiviral Research
dc.subjectWest Nile Virus protease inhibitors
dc.subjectMolecular modeling and docking
dc.subjectcompetitive inhibitors of West Nile vrius protease
dc.subjectStructure activity relationship study among 8 hydroxyquinoline derivatives
dc.titleCharacterization of the 8-hydroxyquinoline scaffold for inhibitors of West Nile virus serine protease
dc.typeArticle
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