title: Discovery of boceprevir, a direct-acting NS3/4A protease inhibitor for treatment of chronic hepatitis C infections.
abstract: Hepatitis C virus (HCV) infection is the primary cause of liver cirrhosis and hepatocellular carcinoma. HCV is the leading cause of liver transplantation in the USA, and more than 200 million people worldwide are infected with HCV. Before the introduction of NS3 protease inhibitors, the standard of care was treatment with peg-interferon and ribavirin. Recent developments in virology have identified many novel targets in the HCV genome, allowing the development of direct-acting antivirals. In this article, I outline the discovery and development of boceprevir, the first HCV NS3/4A protease inhibitor approved for treatment of genotype 1 HCV infection. Boceprevir greatly improves the sustained virologic response (SVR) and provides new hope for treating genotype 1 infections.
authors.affiliation: Merck Research Laboratories, Mail Stop RY121E-28, 126 East Lincoln Avenue, Rahway, NJ 07065-0900, USA. srikanth.venkatraman@merck.com
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D055808:Drug Discovery; D006526:Hepatitis C / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011480:Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011487:Protein Conformation; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011392:Proline; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide