title: Hepatitis C virus NS3/4a protease inhibitors.
abstract: Hepatitis C virus (HCV) infection is a major health issue around the world and HCV NS3/4a protease inhibitors have been the focus of intensive research for the past 20 years. From the first identification of substrate-derived peptide inhibitors to the complex, macrocyclic compounds, including paritaprevir and grazoprevir, that are currently available, the field has used structure-based design to confront the issues of potency, resistance and pharmacokinetics. Numerous breakthrough structures from a multitude of companies have led to compounds that are now key components of combination therapies with cure rates of >90%. Herein, we detail the compounds that have advanced to clinical trials including their design and their impact on the NS3/4a protease field.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, WP14-2, West Point, PA 19486, USA. Electronic address: john_mccauley@merck.com.
authors.forename: John A
authors.initials: JA
authors.lastname: McCauley
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, WP14-2, West Point, PA 19486, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Rudd
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D011480:Protease Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; 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