300 Sensitivity of NS3 serine proteases from various hepatitis C virus genotypes to the antiviral compound BILN 2061

Thibeault, Diane; Bousquet, Christiane; Gingras, Rock; Lagacé, Lisette; Maurice, Roger; White, Peter W.; Lamarre, Daniel

doi:10.1016/s0270-9139(03)80343-9

Cited by 2 publications

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“…It is a conformationally constrained macrocyclic tripeptide derived from optimization of an amino-terminal hexapeptide cleavage product through peptidomimetic rational drug design. The inhibitor displays potent, competitive and reversible inhibition of NS3/4A protease with the dissociation constant of an inhibitor (K i ) against genotype 1a, 1b, 2ac, 2b and 3a of 1.5, 1.6, 86, 83 and 90 nM, respectively, in biochemical assays [80]. The potency of the inhibitor was confirmed using HCV subtype 1a and -b replicons with an EC 50 of 3 and 4 nM, respectively [63].…”

Section: Ns3/4a Protease Inhibitormentioning

confidence: 85%

Hepatitis C drug discovery: in vitro and in vivo systems and drugs in the pipeline

Huang¹,

Deshpande²

2004

Expert Review of Anti-infective Therapy

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The combination therapy of ribavirin and pegylated interferon-alpha for hepatitis C has significant side effects, is often poorly tolerated and is ineffective in many patients, despite causing impressive improvement in the sustained virological response. Discovery and development of more effective and well-tolerated antihepatitis C virus drugs are clearly in great demand. During the past few years, remarkable advances have been made in the establishment of in vitro and in vivo systems. Armed with these systems, a wave of specific antihepatitis C virus compounds have been discovered and are moving into the clinical phase. More effective combination therapies with specific antivirals are predicted to emerge in the near future for the treatment of hepatitis C.

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Section: Ns3/4a Protease Inhibitormentioning

confidence: 85%

Hepatitis C drug discovery: in vitro and in vivo systems and drugs in the pipeline

Huang¹,

Deshpande²

2004

Expert Review of Anti-infective Therapy

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“…These apparent discrepancies between IC 50 values could partly reflect the effects of the helicase domain on the catalytic efficiency and discrimination of the substrate/ligand molecular recognition elements of the NS3 protease; however, differences in the assay conditions used for each protein construct could also play a role. 42 In parallel with the above SAR studies, the interactions of the NS3 protease domain with ligand 6 were also explored by NMR and computational chemistry. 43,44 Transferred nuclear Overhauser effects and transferred 13 C spin-lattice relaxation NMR experiments indicated that peptide 6 adopts an extended ␤-strand conformation and was extensively rigidified upon binding to the NS3.…”

Section: Lead Optimization Of a Substate-based Hexapeptidementioning

confidence: 99%

The design of a potent inhibitor of the hepatitis C virus NS3 protease: BILN 2061—From the NMR tube to the clinic

Tsantrizos

2004

Biopolymers

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The virally encoded serine protease NS3/NS4A is essential to the life cycle of the hepatitis C virus (HCV), an important human pathogen causing chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma. Until very recently, the design of inhibitors for the HCV NS3 protease was limited to large peptidomimetic compounds with poor pharmacokinetic properties, making drug discovery an extremely challenging endeavor. In our quest for the discovery of a small-molecule lead that could block replication of the hepatitis C virus by binding to the HCV NS3 protease, the critical protein-polypeptide interactions between the virally encoded NS3 serine protease and its polyprotein substrate were investigated. Lead optimization of a substrate-based hexapeptide, guided by structural data, led to the understanding of the molecular dynamics and electronic effects that modulate the affinity of peptidomimetic ligands for the active site of this enzyme. Macrocyclic beta-strand scaffolds were designed that allowed the discovery of potent, highly selective, and orally bioavailable compounds. These molecules were the first HCV NS3 protease inhibitors reported that inhibit replication of HCV subgenomic RNA in a cell-based replicon assay at low nanomolar concentrations. Optimization of their biopharmaceutical properties led to the discovery of the clinical candidate BILN 2061. Oral administration of BILN 2061 to patients infected with the hepatitis C genotype 1 virus resulted in an impressive reduction of viral RNA levels, establishing proof-of-concept for HCV NS3 protease inhibitors as therapeutic agents in humans.

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300 Sensitivity of NS3 serine proteases from various hepatitis C virus genotypes to the antiviral compound BILN 2061

Cited by 2 publications

References 0 publications

Hepatitis C drug discovery: in vitro and in vivo systems and drugs in the pipeline

Hepatitis C drug discovery: in vitro and in vivo systems and drugs in the pipeline

The design of a potent inhibitor of the hepatitis C virus NS3 protease: BILN 2061—From the NMR tube to the clinic

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