Structure-activity relationships for the selectivity of hepatitis C virus NS3 protease inhibitors

Poliakov, AntonUppsala universitet,Institutionen för naturvetenskaplig biokemi (författare)

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.

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
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
Biokemi

Johansson, AnjaUppsala universitet,Avdelningen för organisk farmaceutisk kemi(Swepub:uu)anjajoha (författare)
Åkerblom, EvaUppsala universitet,Avdelningen för organisk farmaceutisk kemi (författare)
Oscarsson, Karin (författare)
Samuelsson, Bertil (författare)
Hallberg, AndersUppsala universitet,Avdelningen för organisk farmaceutisk kemi(Swepub:uu)andehall (författare)
Danielson, HelenaUppsala universitet,Institutionen för naturvetenskaplig biokemi(Swepub:uu)helenads (författare)
Uppsala universitetInstitutionen för naturvetenskaplig biokemi (creator_code:org_t)

Ingår i:Biochimica et Biophysica Acta: Elsevier BV1672:1, s. 51-590006-30021878-24340304-4165

Av författaren/redakt...: Poliakov, Anton; Johansson, Anja; Åkerblom, Eva; Oscarsson, Karin; Samuelsson, Bert ...; Hallberg, Anders; visa fler...; Danielson, Helen ...; visa färre...

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