Structure-activity relationships for the selectivity of hepatitis C virus NS3 protease inhibitors
2004 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, Vol. 1672, no 1, 51-59 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2004. Vol. 1672, no 1, 51-59 p.
Hepacivirus/chemistry/*enzymology/metabolism, Protease Inhibitors/*pharmacology, Research Support; Non-U.S. Gov't, Structure-Activity Relationship, Viral Nonstructural Proteins/antagonists & inhibitors/*chemistry/*metabolism
Biochemistry and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-91490DOI: 10.1016/j.bbagen.2004.02.008PubMedID: 15056493OAI: oai:DiVA.org:uu-91490DiVA: diva2:164243