title: Tetrapeptides as potent protease inhibitors of Hepatitis C Virus full-length NS3 (protease-helicase/NTPase).
abstract: A library of tetrapeptides was evaluated for Hepatitis C Virus NS3 protease inhibitor activity in an in vitro assay system comprising the native bifunctional full-length NS3 (protease-helicase/NTPase) protein. Tetrapeptides with K(i) values in the high nanomolar range were identified, for example Suc-Chg-Glu-2-Nal-Cys (K(i)=0.27+/-0.03 microM) and Suc-Dif-Glu-Glu-Cys (K(i)=0.40+/-0.10 microM). Furthermore, it was shown that the inhibitory potencies are not affected significantly by assay ionic strength. As suggested by molecular modelling, potential binding interactions of the tetrapeptide inhibitors with the helicase domain might explain the data and structure-activity relationships thus obtained. Hence, we postulate that the full-length NS3 assay is a relevant system for inhibitor identification, offering new opportunities for inhibitor design.
authors.affiliation: Department of Medicinal Chemistry, Uppsala University, BMC, Box 574, SE-751 23 Uppsala, Sweden.
authors.forename: Anja
authors.initials: A
authors.lastname: Johansson
authors.forename: Anton
authors.initials: A
authors.lastname: Poliakov
authors.forename: Eva
authors.initials: E
authors.lastname: Akerblom
authors.forename: Gunnar
authors.initials: G
authors.lastname: Lindeberg
authors.forename: Susanne
authors.initials: S
authors.lastname: Winiwarter
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: U Helena
authors.initials: UH
authors.lastname: Danielson
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
mesh_terms: D001665:Binding Sites; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D009994:Osmolar Concentration; D019151:Peptide Library; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; 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; D019151:Peptide Library; 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