title: NMR structural characterization of peptide inhibitors bound to the Hepatitis C virus NS3 protease: design of a new P2 substituent.
abstract: A comparative NMR conformational analysis of three distinct tetrapeptide inhibitors of the Hepatitis C NS3 protease that differ at the 4-aryloxy-substituted P2 proline position was undertaken. Specifically, transferred nuclear Overhauser effect experiments in combination with restrained systematic conformational searches were used to characterize the orientation of the P2 aryl substituents of these inhibitors when bound to the NS3 protease. Differences between free and bound conformations were also investigated. Analysis of the results allowed the design of a new P2 aromatic substituent, which significantly increased the potency of our inhibitors. The bound conformation of a specific competitive inhibitor having this novel P2 substituent is also described, along with a model of this inhibitor bound to the NS3 protease. This NS3 protease/inhibitor complex model also supports a hypothetical stabilization role for the P2 residue of the substrates and/or inhibitors and further elucidates the subtle details of the binding of the P2 residue of substrate-based inhibitors.
authors.affiliation: Department of Chemistry, Boehringer Ingelheim (Canada) Ltd., Research & Development, 2100 Cunard Street, Laval, Québec, Canada H7S 2G5. ngoudreau@lav.boeringer-ingelheim.com
authors.forename: Nathalie
authors.initials: N
authors.lastname: Goudreau
authors.forename: Dale R
authors.initials: DR
authors.lastname: Cameron
authors.forename: Pierre
authors.initials: P
authors.lastname: Bonneau
authors.forename: Vida
authors.initials: V
authors.lastname: Gorys
authors.forename: Céline
authors.initials: C
authors.lastname: Plouffe
authors.forename: Martin
authors.initials: M
authors.lastname: Poirier
authors.forename: Daniel
authors.initials: D
authors.lastname: Lamarre
authors.forename: Montse
authors.initials: M
authors.lastname: Llinas-Brunet
mesh_terms: D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; 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: D009842:Oligopeptides; D011392:Proline; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases