title: Structure-activity relationships for the selectivity of hepatitis C virus NS3 protease inhibitors.
abstract: The selectivity of hepatitis C virus (HCV) non-structural protein 3 (NS3) protease inhibitors was determined by evaluating their inhibitory effect on other serine proteases (human leukocyte elastase (HLE), porcine pancreatic elastase (PPE), bovine pancreatic chymotrypsin (BPC)) and a cysteine protease (cathepsin B). For these peptide inhibitors, the P1-side chain and the C-terminal group were the major determinants of selectivity. Inhibitors with electrophilic C-terminal residues were generally non-selective while compounds with non-electrophilic C-terminal residues were more selective. Furthermore, compounds with P1 aminobutyric acid residues were non-selective, while 1-aminocyclopropane-1-carboxylic acid (ACPC) and norvaline-based inhibitors were generally selective. The most potent and selective inhibitors of NS3 protease tested contained a non-electrophilic phenyl acyl sulfonamide C-terminal residue. HLE was most likely to be inhibited by the HCV protease inhibitors, in agreement with similar substrate specificities for these enzymes. The identified structure-activity relationships for selectivity are of significance for design of selective HCV NS3 protease inhibitors.
authors.affiliation: Department of Biochemistry, Uppsala University, BMC, Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: Anton
authors.initials: A
authors.lastname: Poliakov
authors.forename: Anja
authors.initials: A
authors.lastname: Johansson
authors.forename: Eva
authors.initials: E
authors.lastname: Akerblom
authors.forename: Karin
authors.initials: K
authors.lastname: Oscarsson
authors.forename: Bertil
authors.initials: B
authors.lastname: Samuelsson
authors.forename: Anders
authors.initials: A
authors.lastname: Hallberg
authors.forename: U Helena
authors.initials: UH
authors.lastname: Danielson
mesh_terms: D016174:Hepacivirus / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: 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