Highly potent and selective peptide-based inhibitors of the hepatitis C virus serine protease: towards smaller inhibitors.
Structure-activity studies on a hexapeptide N-terminal cleavage product of a dodecamer substrate led to the identification of very potent and highly specific inhibitors of the HCV NS3 protease/NS4A cofactor peptide complex. The largest increase in potency was accomplished by the introduction of a (4R)-naphthalen-1-yl-4-methoxy substituent to the P2 proline. N-Terminal truncation resulted in tetrapeptides containing a C-terminal carboxylic acid, which exhibited low micromolar activity against the HCV serine protease.
Llinàs-Brunet
M
M
Boehringer Ingelheim, Canada Ltd, Research and Development, Laval, Quebec. mllinas@lav.boehringer-ingelheim.com
Bailey
M
M
Fazal
G
G
Ghiro
E
E
Gorys
V
V
Goulet
S
S
Halmos
T
T
Maurice
R
R
Poirier
M
M
Poupart
M A
MA
Rancourt
J
J
Thibeault
D
D
Wernic
D
D
Lamarre
D
D
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D002401:Cathepsin B; D002918:Chymotrypsin; D019272:Leukocyte Elastase; D009842:Oligopeptides; D010196:Pancreatic Elastase; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C093542:NS4 protein, hepatitis C virus