Evolution, synthesis and SAR of tripeptide alpha-ketoacid inhibitors of the hepatitis C virus NS3/NS4A serine protease.
N-terminal truncation of the hexapeptide ketoacid 1 gave rise to potent tripeptide inhibitors of the hepatitis C virus NS3 protease/NS4A cofactor complex. Optimization of these tripeptides led to ketoacid 30 with an IC50 of 0.38 microM. The SAR of these tripeptides is discussed in the light of the recently published crystal structures of a ternary tripetide/NS3/NS4A complexes.
Colarusso
Stefania
S
Department of Chemistry, IRBM, MRL Rome, Via Pontina Km 30.600, Pomezia, 00040, Rome, Italy.
Gerlach
Benjamin
B
Koch
Uwe
U
Muraglia
Ester
E
Conte
Immacolata
I
Stansfield
Ian
I
Matassa
Victor G
VG
Narjes
Frank
F
D002264:Carboxylic Acids; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D016174:Hepacivirus / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D002264:Carboxylic Acids; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009842:Oligopeptides; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus