Combined X-ray, NMR, and kinetic analyses reveal uncommon binding characteristics of the hepatitis C virus NS3-NS4A protease inhibitor BI 201335.
J Biol Chem
; 286(13): 11434-43, 2011 Apr 01.
Article
em En
| MEDLINE
| ID: mdl-21270126
ABSTRACT
Hepatitis C virus infection, a major cause of liver disease worldwide, is curable, but currently approved therapies have suboptimal efficacy. Supplementing these therapies with direct-acting antiviral agents has the potential to considerably improve treatment prospects for hepatitis C virus-infected patients. The critical role played by the viral NS3 protease makes it an attractive target, and despite its shallow, solvent-exposed active site, several potent NS3 protease inhibitors are currently in the clinic. BI 201335, which is progressing through Phase IIb trials, contains a unique C-terminal carboxylic acid that binds noncovalently to the active site and a bromo-quinoline substitution on its proline residue that provides significant potency. In this work we have used stopped flow kinetics, x-ray crystallography, and NMR to characterize these distinctive features. Key findings include slow association and dissociation rates within a single-step binding mechanism; the critical involvement of water molecules in acid binding; and protein side chain rearrangements, a bromine-oxygen halogen bond, and profound pK(a) changes within the catalytic triad associated with binding of the bromo-quinoline moiety.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oligopeptídeos
/
Inibidores de Proteases
/
Tiazóis
/
Proteínas de Transporte
/
Proteínas não Estruturais Virais
/
Hepacivirus
Limite:
Humans
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article