title: Novel azapeptide inhibitors of hepatitis C virus serine protease.
abstract: Azapeptides are known inhibitors of several serine and cysteine proteases. In seeking different classes of inhibitors for the HCV serine protease, a series of novel azapeptide-based inhibitors were investigated which incorporated noncleavable P1/P1' aza-amino acyl residues. Extensive SAR studies around the P1/P1' aza-amino acyl fragment resulted in the identification of potent and selective inhibitors. Using NMR studies, we have shown that this series of inhibitors bind in a noncovalent competitive fashion to the NS3 protease active site. The bound conformation of one of these new azapeptide-based inhibitors was determined using the transfer NOE technique. Incorporation of these new aza-amino acyl functionalities in the P1 position provided a handle to probe for new interactions in the S' region of the enzyme.
authors.affiliation: Boehringer Ingelheim (Canada) Ltd. Research and Development, 2100 Cunard Street, Laval, Quebec, Canada H7S 2G5. mbailey@lav.boehringer-ingelheim.com
authors.forename: Murray D
authors.initials: MD
authors.lastname: Bailey
authors.forename: Ted
authors.initials: T
authors.lastname: Halmos
authors.forename: Nathalie
authors.initials: N
authors.lastname: Goudreau
authors.forename: Ewen
authors.initials: E
authors.lastname: Lescop
authors.forename: Montse
authors.initials: M
authors.lastname: Llinàs-Brunet
mesh_terms: D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D016174:Hepacivirus / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D001372:Aza Compounds; D010455:Peptides; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases