Information on EC 3.4.21.113 - pestivirus NS3 polyprotein peptidase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
3.4.21.113
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RECOMMENDED NAME
GeneOntology No.
pestivirus NS3 polyprotein peptidase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
Leu is conserved at position P1 for all four cleavage sites. Alanine is found at position P1' of the NS4A-NS4B cleavage site, whereas serine is found at position P1' of the NS3-NS4A, NS4B-NS5A and NS5A-NS5B cleavage sites
show the reaction diagram
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of peptide bond
CAS REGISTRY NUMBER
COMMENTARY hide
37259-58-8
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
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the enzyme is well conserved among the Flaviviridae
malfunction
metabolism
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internal cleavage within the NS3 moiety is a common process that further extends the functional repertoires of the multifunctional NS2-3 or NS3 and represents another level of the complex polyprotein processing of Flaviviridae
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
bovine viral diarrhea virus polyprotein + H2O
?
show the reaction diagram
DPNRKRGWPA + H2O
DPNRKR + GWPA
show the reaction diagram
-
-
-
-
?
DSSTKRGGSW + H2O
DSSTKR + GGSW
show the reaction diagram
-
preferred substrate, 33.5% cleavage, the active protease is able to cleave the substrate at the endoplasmic reticulum membrane in Huh-7 cells
-
-
?
FASGKRSQIG + H2O
FASGKR + SQIG
show the reaction diagram
-
-
-
-
?
KPGLKRGGAK + H2O
KPGLKR + GGAK
show the reaction diagram
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preferred substrate, 34.5% cleavage
-
-
?
LQYTKRGGVL + H2O
LQYTKR + GGVL
show the reaction diagram
-
-
-
-
?
non-structural protein 4-5 + H2O
?
show the reaction diagram
in trans-cleavage assays using NS4-5 as a substrate, NS3p acts as a fully functional protease that is able to process the polyprotein
-
-
?
pGlu-Arg-Thr-Lys-Arg-7-amido-4-methylcoumarin + H2O
?
show the reaction diagram
-
-
-
?
Pyr-RTKR-7-amido-4-methylcoumarin + H2O
Pyr-RTKR + 7-amino-4-methylcoumarin
show the reaction diagram
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-
-
-
?
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
bovine viral diarrhea virus polyprotein + H2O
?
show the reaction diagram
DPNRKRGWPA + H2O
DPNRKR + GWPA
show the reaction diagram
-
-
-
-
?
DSSTKRGGSW + H2O
DSSTKR + GGSW
show the reaction diagram
-
preferred substrate, 33.5% cleavage, the active protease is able to cleave the substrate at the endoplasmic reticulum membrane in Huh-7 cells
-
-
?
FASGKRSQIG + H2O
FASGKR + SQIG
show the reaction diagram
-
-
-
-
?
KPGLKRGGAK + H2O
KPGLKR + GGAK
show the reaction diagram
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preferred substrate, 34.5% cleavage
-
-
?
LQYTKRGGVL + H2O
LQYTKR + GGVL
show the reaction diagram
-
-
-
-
?
non-structural protein 4-5 + H2O
?
show the reaction diagram
P19712
in trans-cleavage assays using NS4-5 as a substrate, NS3p acts as a fully functional protease that is able to process the polyprotein
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-
?
Pyr-RTKR-7-amido-4-methylcoumarin + H2O
Pyr-RTKR + 7-amino-4-methylcoumarin
show the reaction diagram
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-
-
-
?
additional information
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
the presence of the upstream virus-encoded NS2B cofactor is required for NS3 proteinase to exhibit its functional activity
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(1S,5R)-6,6-dichloro-3-[cyclohexyl[[[(1,1-dimethylethyl)amino]carbonyl]amino]acetyl]-N-[1-[1,2-dioxo-2-(2-propenylamino)ethyl]butyl]-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide
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(2-[3-[(12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo-[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carbonyl)amino]-2-oxohexanoylamino]acetylamino)phenylacetic acid
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(2-[3-[(12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo-[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carbonyl)amino]-2-oxohexanoylamino]acetylamino)phenylacetic acid tert-butyl ester
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(2-[3-[(12-cyclohexyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,-13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carbonyl)amino]-2-oxohexanoylamino]acetylamino)phenylacetic acid tert-butyl ester
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1,1-dimethylethyl [1(S)-[[(1R,5S)-2(S)-[[[1-(cyclopropylmethyl)-3-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]-amino]-2-oxoethyl]amino]-2,3-dioxopropyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]carbonyl]-2,2-dimethylpropyl]carbamate
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SCH446211, potent ketoamide inhibitor. Has low oral bioavailability in rats and monkeys, but its subcutaneous pharmacokinetic profile is remarkable, with high AUC and 100% bioavailability in both species
1,1-dimethylethyl [1(S)-[[(1R,5S)-2(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]-4,4,4-trifluorobutyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]carbonyl]-2,2-dimethylpropyl]carbamate
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1,1-dimethylethyl [1(S)-[[(1R,5S)-2-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]pentyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo-[3.1.0]hexan-3-yl]carbonyl]-2,2-dimethylpropyl]carbamate
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1,1-dimethylethyl [1-cyclohexyl-2-[(1S,5R)-6,6-dichloro-2(S)-[[[1-[1,2-dioxo-2-(2-propenylamino) ethyl]butyl]-amino]carbonyl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxoethyl]carbamate
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1,1-dimethylethyl [2-[(1S,5R)-2(S)-[[[1-(2-amino-1,2-dioxoethyl)butyl]amino]carbonyl]-6,6-dichloro-3-azabicyclo[3.1.0]hexan-3-yl]-1(S)-cyclohexyl-2-oxoethyl]-carbamate
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1,1-dimethylethyl[1-cyclohexyl-2-[(1S,5R)-6,6-dichloro-2(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]-butyl]amino]carbonyl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxoethyl]carbamate
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1,3,4-tri-O-galloyl-beta-D-glucose
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polyphenol compound from Saxifraga melanocentra
1,3,6-tri-O-galloyl-beta-D-glucose
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polyphenol compound from Terminalia chebula
1-O-(3-O-galloylgalloyl)-2,3,4-tri-O-galloyl-beta-D-glucose
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polyphenol compound from Saxifraga melanocentra
11-cyclohexyl-10,13-dioxo-2,5-dioxa-9,12-diazatricyclo[13.3.1.16,9]icosa-1(18),15(19),16-triene-8-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)aminooxalyl)-butyl)amide
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12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(cyanophenylmethyl)carbamoyl]methyl)aminooxalyl)butyl)-amide
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12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)aminooxalyl)butyl)amide
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very potent inhibitor, S-isomer and R-isomer
12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid (([1-(2-hydroxy-1-phenylethylcarbamoyl)methyl]aminooxalyl)butyl)-amide
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12-cyclohexyl-11,14-dioxo-2-oxa-6-thia-10,13-diazatricyclo-[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)aminooxalyl)butyl)amide
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12-cyclohexyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]-methyl)aminooxalyl)butyl)amide
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12-cyclohexyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid (1-allylaminooxalylbutyl)amide
-
97% orally bioavailable
12-cyclohexyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid (1-aminooxalylbutyl)amide
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12-cyclohexyl-6,6,11,14-tetraoxo-2-oxa-6lambda6-thia-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)-aminooxalyl)butyl)amide
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12-indan-2-yl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)aminooxalyl)butyl)amide
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12-isopropyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]-methyl)aminooxalyl)butyl)amide
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-
12-sec-butyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]-methyl)aminooxalyl)butyl)amide
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12-tert-butyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)aminooxalyl)butyl)amide
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-
12-tert-butyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)-aminooxalyl)butyl)amide
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2,2,2-trifluoro-1,1-dimethylethyl[2-[(1S,5R)-2(S)-[[[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]amino]-carbonyl]-6,6-dichloro-3-azabicyclo[3.1.0]hexan-3-yl]-1(S)-cyclohexyl-2-oxoethyl]carbamate
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2-methylpropyl [1(S)-cyclohexyl-2-[2(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl]-2-oxoethyl]carbamate
-
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2-methylpropyl [1(S)-[[(3aR,6aR)-4(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]amino]carbonyl]hexahydro-2,2-dimethyl-5H-furo[2,3-c]pyrrol-5-yl]carbonyl]-2,2-dimethylpropyl]carbamate
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2-methylpropyl [1(S)-[[(3aR,6aS)-1(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]amino]carbonyl]hexahydro-5,5-dimethylcyclopenta[c]pyrrol-2(1H)-yl]carbonyl]-2,2-dimethylpropyl]carbamate
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2-methylpropyl [1-cyclohexyl-2-[2-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]butyl]amino]carbonyl]-4(S)-[(1,1-dimethylethyl)thio]-1-pyrrolidinyl]-2-oxoethyl]carbamate
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2-methylpropyl [1-cyclohexyl-2-[3(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]butyl]amino]carbonyl]-6,10-dithia-2-azaspiro[4.5]-decan-2-yl]-2-oxoethyl]carbamate
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2-O-(4-O-galloylgalloyl)-1,3,4-tri-O-galloyl-beta-D-glucose
-
polyphenol compound from Rhodiola kirilowii
3,3'-digalloylprocyanidin B2
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nonpeptide inhibitor of NS3-SP from Rhodiola kirilowii. Methylation and acylation of hydroxyl groups cause a decrease of activity
3,3'-digalloylproprodelphinidin B2
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nonpeptide inhibitor of NS3-SP from Rhodiola kirilowii. Methylation and acylation of hydroxyl groups cause a decrease of activity
3,6-di-O-galloyl-beta-D-glucose
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polyphenol compound from Saxifraga melanocentra
3-[2-(3-tert-butyl-ureido)-2-indan-2-yl-acetyl]-6,6-dichloro-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid(2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethyl)-amide
-
-
3-[2-(3-tert-butyl-ureido)-3,3-dimethyl-butyryl]-6,6-dichloro-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid(2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethyl)-amide
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4-phenylphenacetyl-L-Lys-L-Lys-agmatine
-
competitive inhibitor
5,5-dimethyl-11,14-dioxo-12-phenyl-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]-methyl)aminooxalyl)butyl)amide
-
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5-cyclohexyl-3,6-dioxo-11,16-dioxa-4,7-diazatricyclo[15.3.1.17,10]-docosa-1(21),17,19-triene-8-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)aminooxalyl)butyl)-amide
-
-
6,6-dichloro-3-[2-cyclohexyl-2-(3-cyclohexyl-ureido)-acetyl]-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid(2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethyl)-amide
-
-
6-benzenesulfonyl-12-cyclohexyl-11,14-dioxo-2-oxa-6,10,13-triazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]-methyl)aminooxalyl)butyl)amide
-
-
epicatechin-3-O-gallate
-
nonpeptide inhibitor of NS3-SP from Rhodiola kirilowii. Methylation and acylation of hydroxyl groups cause a decrease of activity
epigallocatechin-3-O-gallate
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nonpeptide inhibitor of NS3-SP from Rhodiola kirilowii. Methylation and acylation of hydroxyl groups cause a decrease of activity
N-acetyl-L-Lys-L-Lys-agmatine
-
-
N-[(2-methylpropoxy)carbonyl]-(S)-tert-leucyl-N-[1(S)-[2-[[2-[[2-(dimethylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]-4(R)-methyl-(S)-prolinamide
-
-
N-[(2-methylpropoxy)carbonyl]-(S)-tert-leucyl-n-[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]butyl]-4(R)-(1,1-dimethylethoxy)-(S)-prolinamide
-
-
N-[(2-methylpropoxy)carbonyl]cyclohexylglucyl-N-[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]prolinamide
-
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N-[(2S)-6-amino-1-[(3S)-3-(carbamimidamidomethyl)pyrrolidin-1-yl]-1-oxohexan-2-yl]-N2-(biphenyl-4-ylacetyl)-L-lysinamide
-
-
N2-(biphenyl-4-ylacetyl)-L-lysyl-N-[(2E)-4-carbamimidamidobut-2-en-1-yl]-L-lysinamide
-
-
tert-butyl [(1S)-1-cyclohexyl-2-[(1S,5R)-6,6-dichloro-1-([4-cyclopropyl-1-[([[(1S)-3-(dimethylamino)-3-oxo-1-phenylpropyl]amino]methyl)amino]-3-oxobutyl]carbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-oxoethyl]carbamate
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-
[1-[2-(2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethylcarbamoyl)-6,6-dichloro-3-aza-bicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester
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is the most promising of all inhibitors. Is more potent than SCH 503034. It has excellent potency in both enzyme and replicon assays. Demonstrates good overall pharmacokinetic profile with bioavailability above 10% in rat, monkey, and dog
[2-[2-(2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethylcarbamoyl)-6,6-dichloro-3-aza-bicyclo[3.1.0]hex-3-yl]-1-indan-2-yl-2-oxo-ethyl]-carbamic acid tert-butyl ester
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-
additional information
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0001
(1S,5R)-6,6-dichloro-3-[cyclohexyl[[[(1,1-dimethylethyl)amino]carbonyl]amino]acetyl]-N-[1-[1,2-dioxo-2-(2-propenylamino)ethyl]butyl]-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide
-
-
0.00001
(2-[3-[(12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo-[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carbonyl)amino]-2-oxohexanoylamino]acetylamino)phenylacetic acid
-
-
0.000044
(2-[3-[(12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo-[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carbonyl)amino]-2-oxohexanoylamino]acetylamino)phenylacetic acid tert-butyl ester
-
-
0.000016
(2-[3-[(12-cyclohexyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,-13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carbonyl)amino]-2-oxohexanoylamino]acetylamino)phenylacetic acid tert-butyl ester
-
-
0.0000038
1,1-dimethylethyl [1(S)-[[(1R,5S)-2(S)-[[[1-(cyclopropylmethyl)-3-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]-amino]-2-oxoethyl]amino]-2,3-dioxopropyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]carbonyl]-2,2-dimethylpropyl]carbamate
-
SCH446211
0.000002
1,1-dimethylethyl [1(S)-[[(1R,5S)-2(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]-4,4,4-trifluorobutyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]carbonyl]-2,2-dimethylpropyl]carbamate
-
-
0.00001
1,1-dimethylethyl [1(S)-[[(1R,5S)-2-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]pentyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo-[3.1.0]hexan-3-yl]carbonyl]-2,2-dimethylpropyl]carbamate
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-
0.0009
1,1-dimethylethyl [1-cyclohexyl-2-[(1S,5R)-6,6-dichloro-2(S)-[[[1-[1,2-dioxo-2-(2-propenylamino) ethyl]butyl]-amino]carbonyl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxoethyl]carbamate
-
-
0.00002
1,1-dimethylethyl [2-[(1S,5R)-2(S)-[[[1-(2-amino-1,2-dioxoethyl)butyl]amino]carbonyl]-6,6-dichloro-3-azabicyclo[3.1.0]hexan-3-yl]-1(S)-cyclohexyl-2-oxoethyl]-carbamate
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-
0.000015
1,1-dimethylethyl[1-cyclohexyl-2-[(1S,5R)-6,6-dichloro-2(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]-butyl]amino]carbonyl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxoethyl]carbamate
-
-
0.00003
11-cyclohexyl-10,13-dioxo-2,5-dioxa-9,12-diazatricyclo[13.3.1.16,9]icosa-1(18),15(19),16-triene-8-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)aminooxalyl)-butyl)amide
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-
0.00031
12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(cyanophenylmethyl)carbamoyl]methyl)aminooxalyl)butyl)-amide
-
-
0.000008 - 0.0005
12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)aminooxalyl)butyl)amide
0.00006
12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid (([1-(2-hydroxy-1-phenylethylcarbamoyl)methyl]aminooxalyl)butyl)-amide
-
-
0.00001
12-cyclohexyl-11,14-dioxo-2-oxa-6-thia-10,13-diazatricyclo-[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)aminooxalyl)butyl)amide
-
-
0.000006
12-cyclohexyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]-methyl)aminooxalyl)butyl)amide
-
-
0.00053
12-cyclohexyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid (1-allylaminooxalylbutyl)amide
-
-
0.00022
12-cyclohexyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid (1-aminooxalylbutyl)amide
-
-
0.0033
12-cyclohexyl-6,6,11,14-tetraoxo-2-oxa-6lambda6-thia-10,13-diazatricyclo[14.3.1 .17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)-aminooxalyl)butyl)amide
-
-
0.00004
12-indan-2-yl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)aminooxalyl)butyl)amide
-
-
0.000019
12-isopropyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]-methyl)aminooxalyl)butyl)amide
-
-
0.00007
12-sec-butyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]-methyl)aminooxalyl)butyl)amide
-
-
0.000015 - 0.00013
12-tert-butyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)aminooxalyl)butyl)amide
0.000017
12-tert-butyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)-aminooxalyl)butyl)amide
-
-
0.000065
2,2,2-trifluoro-1,1-dimethylethyl[2-[(1S,5R)-2(S)-[[[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]amino]-carbonyl]-6,6-dichloro-3-azabicyclo[3.1.0]hexan-3-yl]-1(S)-cyclohexyl-2-oxoethyl]carbamate
-
-
0.00001
2-methylpropyl [1(S)-cyclohexyl-2-[2(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]amino]carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl]-2-oxoethyl]carbamate
-
-
0.00001
2-methylpropyl [1(S)-[[(3aR,6aR)-4(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]amino]carbonyl]hexahydro-2,2-dimethyl-5H-furo[2,3-c]pyrrol-5-yl]carbonyl]-2,2-dimethylpropyl]carbamate
-
-
0.000015
2-methylpropyl [1(S)-[[(3aR,6aS)-1(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]amino]carbonyl]hexahydro-5,5-dimethylcyclopenta[c]pyrrol-2(1H)-yl]carbonyl]-2,2-dimethylpropyl]carbamate
-
-
0.00012
2-methylpropyl [1-cyclohexyl-2-[2-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]butyl]amino]carbonyl]-4(S)-[(1,1-dimethylethyl)thio]-1-pyrrolidinyl]-2-oxoethyl]carbamate
-
-
0.000028
2-methylpropyl [1-cyclohexyl-2-[3(S)-[[[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]butyl]amino]carbonyl]-6,10-dithia-2-azaspiro[4.5]-decan-2-yl]-2-oxoethyl]carbamate
-
-
0.00003
3-[2-(3-tert-butyl-ureido)-2-indan-2-yl-acetyl]-6,6-dichloro-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid(2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethyl)-amide
-
-
0.000007
3-[2-(3-tert-butyl-ureido)-3,3-dimethyl-butyryl]-6,6-dichloro-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid(2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethyl)-amide
-
-
0.00205
4-phenylphenacetyl-L-Lys-L-Lys-agmatine
-
at pH 8.0 in Tris-HCl (10 mM), CHAPS (1 mM) and glycerol (20% v/v), at 25°C
0.000046
5,5-dimethyl-11,14-dioxo-12-phenyl-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]-methyl)aminooxalyl)butyl)amide
-
-
0.000007
5-cyclohexyl-3,6-dioxo-11,16-dioxa-4,7-diazatricyclo[15.3.1.17,10]-docosa-1(21),17,19-triene-8-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)aminooxalyl)butyl)-amide
-
-
0.000015
6,6-dichloro-3-[2-cyclohexyl-2-(3-cyclohexyl-ureido)-acetyl]-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid(2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethyl)-amide
-
-
0.000036
6-benzenesulfonyl-12-cyclohexyl-11,14-dioxo-2-oxa-6,10,13-triazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]-methyl)aminooxalyl)butyl)amide
-
-
0.00014
N-[(2-methylpropoxy)carbonyl]-(S)-tert-leucyl-N-[1(S)-[2-[[2-[[2-(dimethylamino)-2-oxo-1-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]-4(R)-methyl-(S)-prolinamide
-
-
0.000019
N-[(2-methylpropoxy)carbonyl]-(S)-tert-leucyl-n-[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]amino]-1,2-dioxoethyl]butyl]-4(R)-(1,1-dimethylethoxy)-(S)-prolinamide
-
-
0.01
N-[(2-methylpropoxy)carbonyl]cyclohexylglucyl-N-[1-[2-[[2-[[2-(dimethylamino)-2-oxo-1(S)-phenylethyl]amino]-2-oxoethyl]-amino]-1,2-dioxoethyl]butyl]prolinamide
-
-
0.0612
N-[(2S)-6-amino-1-[(3S)-3-(carbamimidamidomethyl)pyrrolidin-1-yl]-1-oxohexan-2-yl]-N2-(biphenyl-4-ylacetyl)-L-lysinamide
-
at pH 8.0 in Tris-HCl (10 mM), CHAPS (1 mM) and glycerol (20% v/v), at 25°C
0.02
N2-(biphenyl-4-ylacetyl)-L-lysyl-N-[(2E)-4-carbamimidamidobut-2-en-1-yl]-L-lysinamide
-
at pH 8.0 in Tris-HCl (10 mM), CHAPS (1 mM) and glycerol (20% v/v), at 25°C
0.000007
tert-butyl [(1S)-1-cyclohexyl-2-[(1S,5R)-6,6-dichloro-1-([4-cyclopropyl-1-[([[(1S)-3-(dimethylamino)-3-oxo-1-phenylpropyl]amino]methyl)amino]-3-oxobutyl]carbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-2-oxoethyl]carbamate
-
-
0.000009
[1-[2-(2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethylcarbamoyl)-6,6-dichloro-3-aza-bicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester
-
-
0.00006
[2-[2-(2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethylcarbamoyl)-6,6-dichloro-3-aza-bicyclo[3.1.0]hex-3-yl]-1-indan-2-yl-2-oxo-ethyl]-carbamic acid tert-butyl ester
-
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.001
1,3,4-tri-O-galloyl-beta-D-glucose
Hepatitis C virus
-
-
0.01009
1,3,6-tri-O-galloyl-beta-D-glucose
Hepatitis C virus
-
-
0.00068
1-O-(3-O-galloylgalloyl)-2,3,4-tri-O-galloyl-beta-D-glucose
Hepatitis C virus
-
-
0.00024
12-cyclohexyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]methyl)aminooxalyl)butyl)amide
Hepatitis C virus
-
S-isomer
0.00013
12-cyclohexyl-5,5-dimethyl-11,14-dioxo-2,6-dioxa-10,13-diazatricyclo[14.3.1.17,10]henicosa-1(19),16(20),17-triene-9-carboxylic acid ((([1-(dimethylcarbamoylphenylmethyl)carbamoyl]-methyl)aminooxalyl)butyl)amide
Hepatitis C virus
-
-
0.0008
2-O-(4-O-galloylgalloyl)-1,3,4-tri-O-galloyl-beta-D-glucose
Hepatitis C virus
-
-
0.00091
3,3'-digalloylprocyanidin B2
Hepatitis C virus
-
-
0.00077
3,3'-digalloylproprodelphinidin B2
Hepatitis C virus
-
-
0.9497
3,6-di-O-galloyl-beta-D-glucose
Hepatitis C virus
-
-
0.0047
4-phenylphenacetyl-L-Lys-L-Lys-agmatine
West Nile virus
-
at pH 8.0 in Tris-HCl (10 mM), CHAPS (1 mM) and glycerol (20% v/v), at 25°C
0.01855
epicatechin-3-O-gallate
Hepatitis C virus
-
-
0.00851
epigallocatechin-3-O-gallate
Hepatitis C virus
-
-
0.0182
N-acetyl-L-Lys-L-Lys-agmatine
West Nile virus
-
at pH 8.0 in Tris-HCl (10 mM), CHAPS (1 mM) and glycerol (20% v/v), at 25°C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
PDB
SCOP
CATH
ORGANISM
UNIPROT
Classical swine fever virus (strain Alfort)
Classical swine fever virus (strain Alfort)
Classical swine fever virus (strain Alfort)
Classical swine fever virus (strain Alfort)
Classical swine fever virus (strain Alfort)
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
proteolytic modification
-
autocatalytic intramolecular cleavages of the enzyme, overview. One cleavable peptide bond occurs between Leu1781 and Met1782, giving rise to a helicase subunit of 55 kDa and, depending on the substrate, a NS2-3 fragment of 78 kDa, or a NS3 protease subunit of 26 kDa. A second intramolecular cleavage is mapped to the Leu1748/Lys1749 peptide bond that yields a proteolytically inactive NS3 fragment. Deletion of either of the cleavage site residues resultsin a loss ofRNAinfectivity, indicating the functional importance of amino acid identity at the respective positions
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
crystal structure of inhibitors bound to the protease, show close interaction of the macrocycle with the Ala156 methyl group and S4 pocket
-
crystal structure of SCH446211 bound to NS3/NS4A. The P1 (S)-diastereomer is the active component. A reversible covalent bond is formed between the enzyme active site serine (Ser139) hydroxyl and the ketone carbonyl of the inhibitor. The resulting oxygen anion is stabilized by hydrogen bonding with His57. P3 tert-butyl glycine makes hydrophobic contact with the S3 pocket. The NH of the P3 carbamate and the carbonyl at P3 make H bonds with Ala-157. The P2 dimethyl-cyclopropyl proline adopts a bent conformation, placing the two methyl groups in close proximity to Arg-155. The cyclopropyl alanine residue at P1 fits well in the shallow hydrophobic S1 pocket. The P1' glycine moiety does not H bond with the enzyme backbone but allows the P1-P2' residues to form a “C-clamp” that wraps around the side chain of lysine 136 for improved overall binding
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
by affinity chromatography
-
on nickel column and by gel filtration
-
using HiTrap Co2+-chelating chromatography
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
complete genomic nucleotide sequence
expressed in Escherichia coli as a His-tagged fusion protein
into plasmid pMANS34NSH and expressed in Escherichia coli JM109. Chimeric plasmid pCI-neo-NS3/4A-SEAP expressed in Cos-7 cells
-
into vectors pET15b and pET-SUMO
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D1686G
-
mutation does not induce obvious changes in processing
D1695A
-
mutation does not induce obvious changes in processing
S1752C
-
mutant enzyme exhibits only cleavage activity at the NS3/4A site
S1752T
-
mutant enzyme exhibits only cleavage activity at the NS3/4A site; mutant enzyme still shows residual activity
H51A
mutant shows inactivated proteolytic activity
K48A
to prevent its self-cleavage an autolytic site-deficient mutant is generated
S135A
-
inactive
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
medicine
-
NS3 protease domain is essential for the process of viral RNA replication and, given its electrostatic contribution to RNA binding, it may also assist in packaging of the viral RNA