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, protease inhibitor, antiviral therapy, VX-950, α-ketoamide, reversible, covalent
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