title: Design and synthesis of depeptidized macrocyclic inhibitors of hepatitis C NS3-4A protease using structure-based drug design.
abstract: Hepatitis C virus (HCV) NS3, when bound to NS-4A cofactor, facilitates development of mature virons by catalyzing cleavage of a polyprotein to form functional and structural proteins of HCV. The enzyme has a shallow binding pocket at the catalytic site, making development of inhibitors difficult. We have designed, preorganized, and depeptidized macrocyclic inhibitors from P(4) to P(2)' and optimized binding to 0.1 microM. The structure of an inhibitor bound to the enzyme was also solved.
authors.affiliation: Schering Plough Research Institute, K-15, MS-3545, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Srikanth.Venkatraman@spcorp.com
authors.forename: Srikanth
authors.initials: S
authors.lastname: Venkatraman
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
authors.forename: Viyyoor M
authors.initials: VM
authors.lastname: Girijavallabhan
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Madison
authors.forename: Nanua H
authors.initials: NH
authors.lastname: Yao
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Prongay
authors.forename: Nancy
authors.initials: N
authors.lastname: Butkiewicz
authors.forename: John
authors.initials: J
authors.lastname: Pichardo
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D016174:Hepacivirus / Q000201:enzymology*; D006860:Hydrogen Bonding; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D047028:Macrocyclic Compounds; D010455:Peptides; 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