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

Abstract

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.

NMR Spectroscopy for Studying Interactions of Bioactive Molecules

“…Tsantrizos et al [101] used SAR by NMR to optimise small-molecule hepatitis C virus NS3 protease inhibitors. The observed results have shown that the binding affinity and potency were highly dependent on the ring size, the stereochemistry of each chiral centre and the electrostatic potential of the aromatic substituents.…”

Mutations Conferring Resistance to a Hepatitis C Virus (HCV) RNA-Dependent RNA Polymerase Inhibitor Alone or in Combination with an HCV Serine Protease Inhibitor In Vitro

“…Despite the shallow substrate binding site of the HCV NS3 serine protease, a number of inhibitors of this enzyme have been identified (17,43,55,59). Generally, these inhibitors are substrate-based peptidomimetic compounds.…”

A Novel Class of meso -Tetrakis-Porphyrin Derivatives Exhibits Potent Activities against Hepatitis C Virus Genotype 1b Replicons In Vitro

“…Successful examples of small-molecule inhibitors include the protease inhibitors telaprevir (VX-950) and boceprevir (SCH503034), the nucleoside polymerase inhibitor R7128, and the nonnucleoside NS5B inhibitor VCH-222. The macrocyclic inhibitor of NS3, BILN 2061, despite being suspended in clinical development, is a proof-of-principle peptidomimetic compound that was designed to mimic the conformation of substrate-based hexapeptides bound to NS3 and is active both in vitro and in vivo (18,36). In the present study, we report the development of tetracarboxyphenylporphyrins for feasible interaction with biomolecules involved in HCV replication.…”