The design and enzyme-bound crystal structure of indoline based peptidomimetic inhibitors of hepatitis C virus NS3 protease.
The design of a series of peptidomimetic inhibitors of the hepatitis C virus NS3 protease is described. These inhibitors feature an indoline-2-carboxamide as a novel heterocyclic replacement for the P3 amino acid residue and N-terminal capping group of tripeptide based inhibitors. The crystal structure of the ternary NS3/NS4A/inhibitor complex for the most active molecule in this series highlights its suitability as an N-terminal capping group of a dipeptide inhibitor of the NS3 protease.
Ontoria
Jesus M
JM
IRBM-MRL Rome, Via Pontina km 30,600, 00040 Rome, Italy.
Di Marco
Stefania
S
Conte
Immacolata
I
Di Francesco
M Emilia
ME
Gardelli
Cristina
C
Koch
Uwe
U
Matassa
Victor G
VG
Poma
Marco
M
Steinkühler
Christian
C
Volpari
Cinzia
C
Harper
Steven
S
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D016174:Hepacivirus / Q000201:enzymology*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D011485:Protein Binding; D013237:Stereoisomerism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D007211:Indoles; D009842:Oligopeptides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases