title: A systematic approach to the optimization of substrate-based inhibitors of the hepatitis C virus NS3 protease: discovery of potent and specific tripeptide inhibitors.
abstract: The inadequate efficacy and tolerability of current therapies for the infectious liver disease caused by the hepatitis C virus have warranted significant efforts in the development of new therapeutics. We have previously reported competitive peptide inhibitors of the NS3 serine protease based on the N-terminal cleavage products of peptide substrates. A detailed study of the interactions of these substrate-based inhibitors with the different subsites of the serine protease active site led to the discovery of novel residues that increased the affinity of the inhibitors. In this paper, we report the combination of the best binding residues in a tetrapeptide series that resulted in extremely potent inhibitors that bind exquisitely well to this enzyme. A substantial increase in potency was obtained with the simultaneous introduction of a 7-methoxy-2-phenyl-4-quinolinoxy moiety at the gamma-position of the P2 proline and a tert-leucine as a P3 residue. The increase in potency allowed for the further truncation and led to the identification of tripeptide inhibitors. Structure activity relationship studies on this inhibitor series led to the identification of carbamate-containing tripeptides that are able to inhibit replication of subgenomic HCV RNA in cell culture with potencies below 1 microM. This inhibitor series has the potential of becoming antiviral agents for the treatment of HCV infections.
authors.affiliation: Department of Chemistry, Research and Development, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard Street, Laval, Québec, H7S 2G5, Canada. mllinas@lav.boehringer-ingelheim.com
authors.forename: Montse
authors.initials: M
authors.lastname: Llinàs-Brunet
authors.forename: Murray D
authors.initials: MD
authors.lastname: Bailey
authors.forename: Elise
authors.initials: E
authors.lastname: Ghiro
authors.forename: Vida
authors.initials: V
authors.lastname: Gorys
authors.forename: Ted
authors.initials: T
authors.lastname: Halmos
authors.forename: Martin
authors.initials: M
authors.lastname: Poirier
authors.forename: Jean
authors.initials: J
authors.lastname: Rancourt
authors.forename: Nathalie
authors.initials: N
authors.lastname: Goudreau
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002352:Carrier Proteins / Q000737:chemistry; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D016174:Hepacivirus / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012367:RNA, Viral / Q000096:biosynthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014764:Viral Proteins / Q000737:chemistry; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009842:Oligopeptides; D011804:Quinolines; D012367:RNA, Viral; 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