title: Characterization of the 8-hydroxyquinoline scaffold for inhibitors of West Nile virus serine protease.
abstract: 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 IC(50) value of 2.01 ± 0.08 μM using the tetra-peptide substrate was determined to be 5.8 μM. This compound inhibits the WNV NS2B/NS3pro by a competitive mode of inhibition which is supported by molecular modeling.
authors.affiliation: Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Manolya
authors.initials: M
authors.lastname: Ezgimen
authors.forename: Huiguo
authors.initials: H
authors.lastname: Lai
authors.forename: Niklaus H
authors.initials: NH
authors.lastname: Mueller
authors.forename: Kyungae
authors.initials: K
authors.lastname: Lee
authors.forename: Gregory
authors.initials: G
authors.lastname: Cuny
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Padmanabhan
mesh_terms: D001665:Binding Sites; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015125:Oxyquinoline / Q000737:chemistry / Q000494:pharmacology*; D057057:Serine Proteases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014901:West Nile Fever / Q000821:virology*; D014902:West Nile virus / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics
chemical_list: D015842:Serine Proteinase Inhibitors; D014764:Viral Proteins; D015125:Oxyquinoline; D057057:Serine Proteases