Inhibition of hepatitis C virus NS3 protease activity by product-based peptides is dependent on helicase domain.
Structure activity relationships (SARs) of product-based inhibitors of hepatitis C virus NS3 protease were evaluated using an in vitro assay system comprising the native bifunctional full-length NS3 (protease-helicase/NTPase). The results were compared to previously reported data derived from the corresponding NS3 protease domain assay. Shortening the length of the protease inhibitors from hexapeptides to tripeptides revealed that the decrease in potency was much less when determined in the assay system with the full-length NS3 protein. Disagreements in SARs at different positions (P5 P2) were also discovered. Taken together, the results suggest that the impact of the helicase domain upon protease inhibitor binding is substantial.
Johansson
A
A
Department of Organic Pharmaceutical Chemistry, Uppsala University, BMC, Sweden.
Hubatsch
I
I
Akerblom
E
E
Lindeberg
G
G
Winiwarter
S
S
Danielson
U H
UH
Hallberg
A
A
D004268:DNA-Binding Proteins / Q000737:chemistry*; D016174:Hepacivirus / Q000201:enzymology*; D007700:Kinetics; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; 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
D004268:DNA-Binding Proteins; D010446:Peptide Fragments; D015842:Serine Proteinase 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