Characterization of the 8-hydroxyquinoline scaffold for inhibitors of West Nile virus serine protease.
Antiviral Res
; 94(1): 18-24, 2012 Apr.
Article
en En
| MEDLINE
| ID: mdl-22343093
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Virales
/
Fiebre del Nilo Occidental
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Virus del Nilo Occidental
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Inhibidores de Serina Proteinasa
/
Oxiquinolina
Límite:
Humans
Idioma:
En
Revista:
Antiviral Res
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos