If you are experiencing problems downloading PDF or HTML fulltext, our helpdesk recommend clearing your browser cache and trying again. If you need help in clearing your cache, please click here . Still need help? Email help@ingentaconnect.com

Discovery and Development of VX-950, a Novel, Covalent, and Reversible Inhibitor of Hepatitis C Virus NS3.4A Serine Protease

Your trusted access to this article has expired.

$71.00 plus tax (Refund Policy)

Buy Article:


The hepatitis C virus (HCV) NS3.4A protease, which is essential for viral replication, is considered one of the most attractive targets for developing novel anti-HCV therapies. However, discovery of potent and selective smallmolecule inhibitors of HCV NS3.4A protease as oral drug candidates has been hampered by the shallow substrate-binding groove of the protease. Serine trap warheads have been used to covalently anchor inhibitor scaffolds and to increase their affinity to the protease. This review will examine the evolution of covalent inhibitors of the HCV NS3.4A protease from early aldehyde molecules to α-ketoamide inhibitors. Kinetic and structural studies of α-ketoacid and α-ketoamide inhibitors revealed an unusual mechanism of binding in the catalytic site. Optimization of α-ketoamide scaffolds by scientists at Vertex and Eli Lilly led to the discovery of VX-950, a novel, potent, selective inhibitor of HCV NS3.4A protease. VX-950 possesses excellent antiviral activity in both HCV replicon cells and human fetal hepatocytes infected with HCV-positive patient sera. In addition, VX-950 exhibits a favorable pharmacokinetic profile in several animal species and demonstrates potent inhibition of the HCV NS3.4A protease activity in a mouse model. In a recent phase 1b clinical trial, VX-950 was able to rapidly reduce the plasma viral load of patients chronically infected with genotype 1 HCV by a mean ∼3 log10 in 2 days. The median viral load reduction was 4.4 log10 for the best dose group after 14 days of dosing. The pre-clinical profile and early clinical data of VX-950 will be discussed in this review.

Keywords: Hepatitis C virus; NS3.4A serine protease; VX-950; antiviral therapy; covalent; protease inhibitor; reversible; α-ketoamide

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/187152606776056706

Affiliations: Department of Infectious Diseases, Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, Massachusetts 02139, USA.

Publication date: March 1, 2006

Related content



Share Content

Access Key

Free Content
Free content
New Content
New content
Open Access Content
Open access content
Subscribed Content
Subscribed content
Free Trial Content
Free trial content
Cookie Policy
Cookie Policy
ingentaconnect website makes use of cookies so as to keep track of data that you have filled in. I am Happy with this Find out more