History of viral hepatitis

Kalkeri, Gururaj; Kwong, Ann D.

doi:10.1007/978-3-0348-7903-3_1

Cited by 1 publication

(1 citation statement)

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“…In the absence of a small animal model with a robust and consistent HCV infection, a surrogate mouse model for HCV NS3•4A serine protease was developed [62,80,81]. A fused gene encoding the full-length HCV NS3 and NS4A proteins followed by the NS4A/4B cleavage site was fused in frame to secreted placental alkaline phosphatase (SEAP) and inserted into an adenovirus vector.…”

Section: Vx-950 Inhibits Hcv Ns3•4a Protease In a Mouse Modelmentioning

confidence: 99%

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

Lin

Kwong²,

Perni³

2006

IDDT

209

107

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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 small-molecule 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 alpha-ketoamide inhibitors. Kinetic and structural studies of alpha-ketoacid and alpha-ketoamide inhibitors revealed an unusual mechanism of binding in the catalytic site. Optimization of alpha-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 approximately 3 log(10) in 2 days. The median viral load reduction was 4.4 log(10) 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.

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Section: Vx-950 Inhibits Hcv Ns3•4a Protease In a Mouse Modelmentioning

confidence: 99%