Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect

• Published in: Nature (London) Vol. 465; no. 7294; pp. 96 - 100
• Main Authors: Gao, Min, Nettles, Richard E., Belema, Makonen, Snyder, Lawrence B., Nguyen, Van N., Fridell, Robert A., Serrano-Wu, Michael H., Langley, David R., Sun, Jin-Hua, O’Boyle II, Donald R., Lemm, Julie A., Wang, Chunfu, Knipe, Jay O., Chien, Caly, Colonno, Richard J., Grasela, Dennis M., Meanwell, Nicholas A., Hamann, Lawrence G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.05.2010; Springer Nature; Nature Publishing Group
• Subjects: 631/154; 631/326/596; 692/699/255/234/2513/1551; Adolescent; Adult; Amino acids; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - blood; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Biochemical genetics; Biological and medical sciences; Carbamates; Cell Line; Chlorocebus aethiops; Drug Resistance, Viral; Drug therapy; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genetic aspects; Genetics; Genotype; Genotype & phenotype; Genotypes; HeLa Cells; Hepacivirus - drug effects; Hepatitis C; Hepatitis C - drug therapy; Hepatitis C - virology; Hepatitis C virus; Human viral diseases; Humanities and Social Sciences; Humans; Imidazoles - blood; Imidazoles - chemistry; Imidazoles - pharmacology; Infectious diseases; Inhibitory Concentration 50; letter; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Middle Aged; multidisciplinary; Multidisciplinary Sciences; Other diseases. Semiology; Pharmacology. Drug treatments; Pyrrolidines; RNA polymerases; Science; Science & Technology; Science & Technology - Other Topics; Science (multidisciplinary); Testing; Time Factors; Valine - analogs & derivatives; Vero Cells; Viral diseases; Viral diseases of the digestive system; Viral Load - drug effects; Viral Nonstructural Proteins - antagonists & inhibitors; Young Adult; United States; DOMAIN; HEPATITIS-C VIRUS; RNA; NONSTRUCTURAL PROTEINS; Drug; Pharmacotherapy; Hepatic disease; In vitro; Infection; Virus; Chronic; Treatment; Viral disease; Digestive diseases; Antiviral; Flaviviridae; Hepatitis C virus; Hepacivirus; Viral hepatitis C
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature08960

New drugs for hepatitis C The development of direct-acting antiviral agents to treat chronic hepatitis C virus (HCV) infection, much needed clinically, has focused largely on inhibitors of two viral enzymes, the protease NS3 and NS5B, an RNA-dependent RNA polymerase essential for HCV replication. BMS-790052, identified using chemical genetics as a powerful specific HCV inhibitor, is a small-molecule inhibitor of a third viral molecule that has no known enzyme activity, the non-structural protein 5A (NS5A). A research team from Bristol-Myers Squibb this week reports on the discovery and virological profile of BMS-790052 and discloses clinical trial observations with this compound in normal healthy volunteers and HCV-infected subjects. These results establish proof-of-concept for HCV NS5A inhibition as a clinically relevant mechanism. In vitro data point to synergistic interactions with known HCV inhibitors, suggesting that cocktails of antiviral agents may be a viable therapeutic approach. Almost 200 million people worldwide are chronically infected with hepatitis C virus. Current treatments are poorly tolerated and not wholly effective, so new drugs are needed. Here, a potent new inhibitor of hepatitis C virus is described. This inhibitor targets the viral protein NS5A, and shows potential as part of a therapeutic regimen based on a combination of viral inhibitors. The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people 1 . Current therapy relies upon a combination of pegylated interferon-α and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus 2 , 3 . The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B 4 . Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC 50 ) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log 10 reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.