We've updated our Privacy Policy to make it clearer how we use your personal data.

We use cookies to provide you with a better experience. You can read our Cookie Policy here.

Advertisement
Combined X-Ray, NMR and Kinetic Analyses Reveal Uncommon Binding Characteristics of the HCV NS3-NS4a Protease Inhibitor BI 201335
News

Combined X-Ray, NMR and Kinetic Analyses Reveal Uncommon Binding Characteristics of the HCV NS3-NS4a Protease Inhibitor BI 201335

Combined X-Ray, NMR and Kinetic Analyses Reveal Uncommon Binding Characteristics of the HCV NS3-NS4a Protease Inhibitor BI 201335
News

Combined X-Ray, NMR and Kinetic Analyses Reveal Uncommon Binding Characteristics of the HCV NS3-NS4a Protease Inhibitor BI 201335

Read time:
 

Want a FREE PDF version of This News Story?

Complete the form below and we will email you a PDF version of "Combined X-Ray, NMR and Kinetic Analyses Reveal Uncommon Binding Characteristics of the HCV NS3-NS4a Protease Inhibitor BI 201335"

First Name*
Last Name*
Email Address*
Country*
Company Type*
Job Function*
Would you like to receive further email communication from Technology Networks?

Technology Networks Ltd. needs the contact information you provide to us to contact you about our products and services. You may unsubscribe from these communications at any time. For information on how to unsubscribe, as well as our privacy practices and commitment to protecting your privacy, check out our Privacy Policy

Abstract

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.

This article is published online in The Journal of Biological Chemistry and is free to access.

Advertisement