title: Evolution, synthesis and SAR of tripeptide alpha-ketoacid inhibitors of the hepatitis C virus NS3/NS4A serine protease.
abstract: N-terminal truncation of the hexapeptide ketoacid 1 gave rise to potent tripeptide inhibitors of the hepatitis C virus NS3 protease/NS4A cofactor complex. Optimization of these tripeptides led to ketoacid 30 with an IC50 of 0.38 microM. The SAR of these tripeptides is discussed in the light of the recently published crystal structures of a ternary tripetide/NS3/NS4A complexes.
authors.affiliation: Department of Chemistry, IRBM, MRL Rome, Via Pontina Km 30.600, Pomezia, 00040, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Colarusso
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gerlach
authors.forename: Uwe
authors.initials: U
authors.lastname: Koch
authors.forename: Ester
authors.initials: E
authors.lastname: Muraglia
authors.forename: Immacolata
authors.initials: I
authors.lastname: Conte
authors.forename: Ian
authors.initials: I
authors.lastname: Stansfield
authors.forename: Victor G
authors.initials: VG
authors.lastname: Matassa
authors.forename: Frank
authors.initials: F
authors.lastname: Narjes
mesh_terms: D002264:Carboxylic Acids; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D016174:Hepacivirus / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D002264:Carboxylic Acids; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; D014764:Viral 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