Structure of NS3 complexed with a ketoamide inhibitor SCh491762

TERT-BUTYL {(1S)-2-[(1R,2S,5S)-2-({[(1S)-3-AMINO-1-(CYCLOBUTYLMETHYL)-2,3-DIOXOPROPYL]AMINO}CARBONYL)-6,6-DIMETHYL-3-AZABICYCLO[3.1.0]HEX-3-YL]-1-CYCLOHEXYL-2-OXOETHYL}CARBAMATE
Ketoamide Inhibitor SCH491762, bound form

Discovery of the HCV NS3/4A protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key steps in structure-based optimization.

Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide.

Hepatitis C virus NS3-4A serine protease inhibitors: SAR of P'2 moiety with improved potency.

Synthesis and biological activity of macrocyclic inhibitors of hepatitis C virus (HCV) NS3 protease.

Hepatitis C virus NS3-4A serine protease inhibitors: use of a P2-P1 cyclopropyl alanine combination for improved potency.

Mutations conferring resistance to SCH6, a novel hepatitis C virus NS3/4A protease inhibitor. Reduced RNA replication fitness and partial rescue by second-site mutations.

MASMTGGQQMGAPITAYAQQTRGLLGCIITSLTGRDKNQVEGEVQIVSTATQTFLATCINGVCWTVYHGAGTRTIASPKG
PVIQMYTNVDQDLVGWPAPQGSRSLTPCTCGSSDLYLVTRHADVIPVRRRGDSRGSLLSPRPISYLKGSSGGPLLCPAGH
AVGLFRAAVCTRGVAKAVDFIPVENLETTMRSGSHHHHHH

The protein (NS3 complexed with KK-NS4a(21-39)-KK peptide) was at 12-15 mg/ml in 15 mM MES, pH 6.5 1 M NaCl 20 mM b -mercaptoethanol. Hanging Drops were formed by mixing 4:l protein solution with 4:l {0.75-1.0 M NaCl 0.1M Na/K phosphate 0.1 M Mes, pH 5.8-6.1 20 mM b-mercaptoethanol} The drop was equilibrated the drops over 1 ml {(1.25-1.50 M) NaCl - 0.1M Na/K phosphate 0.1 M Mes, pH 5.6-5.8, 20 mM b-mercaptoethanol} , VAPOR DIFFUSION, HANGING DROP, temperature 277K

HEPATITIS C VIRUS NS3-4A SERINE PROTEASE INHIBITORS. SAR OF P2' MOIETY WITH IMPROVED POTENCY.

MUTATIONS CONFERRING RESISTANCE TO SCH6, A NOVEL HEPATITIS C VIRUS NS3/4A PROTEASE INHIBITOR REDUCED RNA REPLICATION FITNESS AND PARTIAL RESCUE BY SECOND SITE MUTATIONS

Hepatitis C Virus, HCV, NS3 protease domain, ketoamide inhibitor, Viral Protein

APITAYAQQTRGLLGCIITSLTGRDKNQVEGEVQIVSTATQTFLATCINGVCWTVYHGAGTRTIASPKGPVIQMYTNVDQ
DLVGWPAPQGSRSLTPCTCGSSDLYLVTRHADVIPVRRQGDSRGSLLSPRPISYLKGSSGGPLLCPAGHAVGLFRAAVCT
RGVAKAVDFIPVENLETTMRS