title: Peptide-based inhibitors of hepatitis C virus full-length NS3 (protease-helicase/NTPase): model compounds towards small molecule inhibitors.
abstract: From L-alpha-aminobutyric acid (Abu) a set of electrophilic and non-electrophilic replacements for the P1 cysteine of substrate and product inhibitors of hepatitis C virus full-length NS3 (protease-helicase/NTPase) serine protease have been synthesised and coupled to a model pentapeptide furnishing a set of hexapeptide inhibitors. Promising inhibitory activities with K(i) values of 0.18 microM (11b, P1 electrophilic alpha,beta-unsaturated ketone), 0.46 microM (12e, P1 electrophilic alkyl ketone) and 0.98 microM (10e, P1 non-electrophilic alkenyl alcohol as diastereomeric mixture). The reference hexapeptide product inhibitor had a K(i) value of 1.54 microM (14, P1 Abu-OH). The electrophilic inhibitors exhibit increased potency as compared with the corresponding product inhibitor, and notably also the non-electrophilic P1 alkenyl alcohol 10e. This represents the first example of non-electrophilic inhibitors that are not P1 amides or product inhibitors.
authors.affiliation: Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Oscarsson
authors.forename: Anton
authors.initials: A
authors.lastname: Poliakov
authors.forename: Stefan
authors.initials: S
authors.lastname: Oscarson
authors.forename: U Helena
authors.initials: UH
authors.lastname: Danielson
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D016174:Hepacivirus / Q000201:enzymology*; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000138:chemical synthesis; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D010455:Peptides; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases