Combined X-ray, NMR and kinetic analyses reveal uncommon binding characteristics of the HCV NS3-NS4A protease inhibitor BI 201335.
J Biol Chem. 2011 Jan 26;
Authors: Lemke CT, Goudreau N, Zhao S, Hucke O, Thibeault D, Llinás-Brunet M, White PW
Hepatitis C virus (HCV) infection, a major cause of liver disease world-wide, 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 HCV 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 non-covalently 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 sidechain rearrangements, a Br-O halogen bond, and profound pKa changes within the catalytic triad associated with binding of the bromo-quinoline moiety.
PMID: 21270126 [PubMed - as supplied by publisher]
NMR Studies Reveal anUnexpected Binding Site for a Redox Inhibitor of AP Endonuclease 1
NMR Studies Reveal anUnexpected Binding Site for a Redox Inhibitor of AP Endonuclease 1
http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/bichaw/0/bichaw.ahead-of-print/bi201071g/aop/images/medium/bi-2011-01071g_0007.gif
Biochemistry
DOI: 10.1021/bi201071g
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