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Information on EC 3.4.21.91 - Flavivirin and Organism(s) West Nile virus and UniProt Accession P06935
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3.4.21.91 FlavivirinSpecify your search results
Word Map
- 3.4.21.91
- polyprotein
- viruses
- ns4a
-
replicons
-
west
- ribavirin
-
anti-hcv
-
direct-acting
-
virologic
-
cirrhosis
-
flaviviral
- boceprevir
- flaviviruses
- encephalitis
-
pegylated
- flaviviridae
- telaprevir
-
subgenomic
-
rna-dependent
-
unwind
-
mosquito-borne
- asunaprevir
-
resistance-associated
-
daclatasvir
- simeprevir
-
hcv-infected
- coronaviruses
-
anti-dengue
- ntpase
-
peptidomimetic
-
nonnucleoside
-
hcv-specific
-
macrodomains
- drug development
-
treatment-naive
-
peginterferon
-
replicase
-
quasispecies
-
interferon-free
-
trans-cleavage
- alphavirus
-
positive-stranded
- sofosbuvir
- analysis
- molecular biology
-
rna-stimulated
- medicine
-
hcv-1b
- synthesis
- gt1
The taxonomic range for the selected organisms is: West Nile virus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Selective hydrolysis of -Xaa-Xaa-/-Yaa- bonds in which each of the Xaa can be either Arg or Lys and Yaa can be either Ser or Ala
Synonyms
ns3 protease, nonstructural protein 3, ns2b-ns3 protease, ns3 serine protease, ns2b-ns3pro, ns2b/ns3 protease, ns3 proteinase, ns3pro, ns2b/ns3, zikv protease, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
NS2B-3 proteinase
-
-
-
-
Yellow fever virus (flavivirus) protease
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
154215-26-6
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
butyloxycarbonyl-Arg-Val-Arg-Arg-7-amido-4-methylcoumarin + H2O
butyloxycarbonyl-Arg-Val-Arg-Arg + 7-amino-4-methylcoumarin
-
-
-
?
pyroglutamic acid-Arg-Thr-Lys-Arg-7-amido-4-methylcoumarin + H2O
pyroglutamic acid-Arg-Thr-Lys-Arg + 7-amino-4-methylcoumarin
-
-
-
?
AQRRGRIG + H2O
AQRR + GRIG
-
three individual batches of the peptide results in AQRR2GRIG 3%, 2%, and 0% cleavages
-
-
?
benzoyl-Nle-Lys-Arg-Arg-4-methylcoumarin 7-amide + H2O
benzoyl-Nle-Lys-Arg-Arg + 7-amino-4-methylcoumarin
-
-
-
-
?
CFP-LQYTKRGGVLWD-YFP + H2O
CFP-LQYTKR + GGVLWD-YFP
-
the artificial substrate contains the natural sequence of the NS2B/NS3 junction and is cleaved efficiently
-
-
?
CFP-SAAQRRGRIGRN-YFP + H2O
CFP-SAAQRR + GRIGRN-YFP
-
cleavage is barely detectable
-
-
?
DSSTKRGGSW + H2O
DSSTKR + GGSW
-
each substrate plasmid contains the ER membrane-anchoring domain, a specific cleavage sequence that includes the P6-P1 P19-P49 residues and a fluorescent reporter group (DsRed)
-
-
?
KPGLKRGGAK + H2O
KPGLKR + GGAK
-
each substrate plasmid contains the ER membrane-anchoring domain, a specific cleavage sequence that includes the P6-P1 P19-P49 residues and a fluorescent reporter group (DsRed)
-
-
?
L-pGlu-L-Arg-L-Thr-L-Lys-L-Arg-7-amido-4-methylcoumarin + H2O
L-pGlu-L-Arg-L-Thr-L-Lys-L-Arg + 7-amino-4-methylcoumarin
-
-
-
-
?
LQYTKRGGVLWD + H2O
LQYTKR + GGVLWD
-
the artificial substrate contains the natural sequence of the NS2B/NS3 junction and is cleaved efficiently
-
-
?
NRKR + GGPA + H2O
NRKRGGPA
-
two individual batches of the peptide results in 78 and 77% cleavages
-
-
?
phenylacetyl-Lys-Lys-Arg-4-nitroanilide + H2O
phenylacetyl-Lys-Lys-Arg + 4-nitroaniline
-
chromogenic substrate
-
-
?
Pyr-Arg-Thr-Lys-Arg-7-amido-4-methylcoumarin + H2O
Pyr-Arg-Thr-Lys-Arg + 7-amino-4-methylcoumarin
-
-
-
-
?
pyroglutamic acid-Arg-Thr-Lys-Arg-4-methylcoumarin 7-amide + H2O
pyroglutamic acid-Arg-Thr-Lys-Arg + 7-amino-4-methylcoumarin
-
-
-
-
?
pyroglutamic acid-L-Arg-L-Thr-L-Lys-L-Arg-7-amido-4-methylcoumarin + H2O
pyroglutamic acid-L-Arg-L-Thr-L-Lys-L-Arg + 7-amino-4-methylcoumarin
-
-
-
-
?
QRRRGGTA + H2O
QRRR + GGTA
-
two individual batches of the peptide results in 58% cleavage
-
-
?
pyroglutamic acid-Arg-Thr-Lys-Arg-7-amido-4-methylcoumarin + H2O
?
-
-
-
-
?
pyroglutamic acid-Arg-Thr-Lys-Arg-7-amido-4-methylcoumarin + H2O
?
-
efficiently cleaved
-
-
?
additional information
?
-
-
NS3 alone triggers the apoptotic pathways involving caspases-8 and -3. Activation of caspase-8 is essential to initiate apoptotic signaling in NS3-expressing cells
-
-
?
additional information
?
-
-
during purification, incomplete autolytic conversion of the 36 kDa NS2B-NS3pro construct into the individual 30 kDa NS3pro and the NS2B sequence (5-6 kDa). Undergoes self-cleavage during expression and purification at the K48G-G site of the glycine linker
-
-
?
additional information
?
-
-
peptides with a similar sequence, including GIKRGETD, LQKRGIVE, LSKRQHPG, LVTAGHGQ, and MLKKGMTT, are completely resistant to proteolysis. Peptides GLKRFGAK, KKQRAGVL, LYKRYGGF, MLKRGMPR, and NQKRYGGF are also not cleaved
-
-
?
additional information
?
-
-
strict substrate specificity, the (K/R)(K/R)R-GG amino acid motif is optimal. Efficiently cleaves peptides derived from the West Nile virus and Dengue virus capsid protein C, from the NS2A/NS2B junction region and NS4B/NS5 junction region and from NS2B/NS3
-
-
?
additional information
?
-
-
the recombinant NS2B-NS3 protease is subject to autolytic cleavage. It catalyzes two autolytic cleavages. The NS2B/NS3 junction is cleaved before protein purification. A second site at Arg4592Gly460 within the C-terminal helicase region of NS3 is cleaved more slowly. Intramolecular cleavage of both the N-terminal site and the internal helicase site of recombinant NS2B-NS3. The artificial substrates CFP-LQYTHMGGVLWD-YFP and CFP-GGGGHMGGVLWD-YFP are not cleaved
-
-
?
additional information
?
-
-
the substrate that corresponds to the NS4B/NS5 junction site is cleaved in trans, whereas the remaining substrates that correspond to the NS2A/NS2B,NS2B/NS3, and NS3/NS4A proprotein junction sites are poorly processed in trans under experimental conditions
-
-
?
additional information
?
-
-
enzyme is highly specific toward lysines at the P2 and P3 positions
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
additional information
?
-
-
NS3 alone triggers the apoptotic pathways involving caspases-8 and -3. Activation of caspase-8 is essential to initiate apoptotic signaling in NS3-expressing cells
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NS2B cofactor
N-terminal region of NS3 and its cofactor NS2B constitute the protease. To function as an active enzyme, the NS3 protease requires the NS2B cofactor. NS2B is an integral membrane protein of 14 kDa that contains three domains: two trans-membrane segments located at the N- and C-termini and a central region of 47 amino acids (spanning amino-acids 49-96) that acts as an essential protein cofactor of the NS3 protease
-
NS2B protein
the G(22) residue and the negatively charged patch D(32)DD(34) of NS2B are part of an important configuration required for NS2B-NS3pro activity
-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2S)-4-[3-(aminomethyl)phenyl]-2-([(2S)-4-[3-(aminomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]amino)-N-[(trans-4-carbamimidamidocyclohexyl)methyl]butanamide
-
-
(2S)-4-[4-(aminomethyl)phenyl]-2-([(2S)-4-[4-(aminomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]amino)-N-[(trans-4-carbamimidamidocyclohexyl)methyl]butanamide
-
-
(2S)-N-[(trans-4-carbamimidamidocyclohexyl)methyl]-4-[3-(carbamimidamidomethyl)phenyl]-2-([(2S)-4-[3-(carbamimidamidomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]amino)butanamide
-
-
(2S)-N-[(trans-4-carbamimidamidocyclohexyl)methyl]-4-[4-(carbamimidamidomethyl)phenyl]-2-([(2S)-4-[4-(carbamimidamidomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]amino)butanamide
-
-
(5-amino-1-phenylsulfonylpyrazol-3-yl) 2-bromobenzoate
-
100.8% inhibition at 0.05 mM
(5-amino-1-phenylsulfonylpyrazol-3-yl)thiophene-2-carboxylate
-
101.4% inhibition at 0.05 mM
1-(2,6-difluorophenyl)-2-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-yl]ethanol
-
-
1-(2,6-difluorophenyl)-2-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-yl]ethanone
-
-
1-(2-fluorophenyl)-2-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-yl]ethanone
-
-
1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-yl 2,6-difluoro-3-methylbenzoate
-
-
1-(4-[3-[4-(furan-3-yl)phenyl]-5-(piperidin-4-ylmethoxy)pyrazin-2-yl]phenyl)methanamine
-
-
2-[[(4-methoxyphenyl)amino]methylidene]cyclohexane-1,3-dione
-
56% inhibition at 0.05 mM
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,3,4-trifluorobenzoate
-
-
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,3,5,6-tetrafluoro-4-methylbenzoate
-
-
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,3,6-trifluorobenzoate
-
-
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,4,5-trifluorobenzoate
-
-
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,4,6-trifluorobenzoate
-
-
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,4-difluorobenzoate
-
-
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,5-difluorobenzoate
-
-
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,6-dichlorobenzoate
-
-
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,6-difluoro-3-methylbenzoate
-
-
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,6-difluorobenzoate
-
-
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2-fluoro-3-(trifluoromethyl)benzoate
-
-
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 3-chlorothiophene-2-carboxylate
-
-
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl thiophene-3-carboxylate
-
-
5-[(E)-2-(2,6-difluorophenyl)ethenyl]-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole
-
-
decanoyl-Arg-Val-Lys-Arg-chloromethylketone
-
completely inhibits autolysis of the NS2B-NS3pro construct
diphenyl (1-[[(benzyloxy)carbonyl]amino]-3-carbamimidamidopropyl)phosphonate
-
-
diphenyl (1-[[(benzyloxy)carbonyl]amino]-4-carbamimidamidobutyl)phosphonate
-
12% inhibition
diphenyl (3-amino-1-[[(benzyloxy)carbonyl]amino]-3-oxopropyl)phosphonate
-
15% inhibition
diphenyl (3-amino-1-[[(benzyloxy)carbonyl]amino]propyl)phosphonate
-
12% inhibition
diphenyl ([4-(1H-benzimidazol-1-yl)phenyl][[(benzyloxy)carbonyl]amino]methyl)phosphonate
-
4% inhibition
diphenyl ([[(benzyloxy)carbonyl]amino][4-(1H-pyrazol-1-yl)phenyl]methyl)phosphonate
-
5% inhibition
diphenyl ([[(benzyloxy)carbonyl]amino][4-(4-methylpiperazin-1-yl)phenyl]methyl)phosphonate
-
3% inhibition
diphenyl ([[(benzyloxy)carbonyl]amino][4-(morpholin-4-yl)phenyl]methyl)phosphonate
-
1% inhibition
diphenyl [(3-aminophenyl)[[(benzyloxy)carbonyl]amino]methyl]phosphonate
-
8% inhibition
diphenyl [(4-aminophenyl)[[(benzyloxy)carbonyl]amino]methyl]phosphonate
-
16% inhibition
diphenyl [1-[[(benzyloxy)carbonyl]amino]-3-(carbamimidoylsulfanyl)propyl]phosphonate
-
22% inhibition
diphenyl [2-(4-aminophenyl)-1-[[(benzyloxy)carbonyl]amino]ethyl]phosphonate
-
11% inhibition
diphenyl [[[(benzyloxy)carbonyl]amino](3-carbamimidamidophenyl)methyl]phosphonate
-
11% inhibition
diphenyl [[[(benzyloxy)carbonyl]amino](3-nitrophenyl)methyl]phosphonate
-
4% inhibition
diphenyl [[[(benzyloxy)carbonyl]amino](4-carbamimidamidophenyl)methyl]phosphonate
-
-
diphenyl [[[(benzyloxy)carbonyl]amino](4-carbamimidoylphenyl)methyl]phosphonate
-
22% inhibition
diphenyl [[[(benzyloxy)carbonyl]amino](4-cyanophenyl)methyl]phosphonate
-
8% inhibition
diphenyl [[[(benzyloxy)carbonyl]amino](4-nitrophenyl)methyl]phosphonate
-
3% inhibition
diphenyl [[[(benzyloxy)carbonyl]amino](6-carbamimidoylnaphthalen-2-yl)methyl]phosphonate
-
12% inhibition
diphenyl [[[(benzyloxy)carbonyl]amino](6-cyanonaphthalen-2-yl)methyl]phosphonate
-
2% inhibition
diphenyl [[[(benzyloxy)carbonyl]amino](carbamimidamido)methyl]phosphonate
-
-
N-(9-ethylcarbazol-3-yl)-2-[(4-ethyl-5-furan-2-yl-1,2,4-triazol-3-yl)sulfanyl]acetamide
-
68.8% inhibition at 0.05 mM
N-[(2S)-1-[[(trans-4-carbamimidamidocyclohexyl)methyl]amino]-4-(4-carbamimidamidophenyl)-1-oxobutan-2-yl]-N2-(phenylacetyl)-L-lysinamide
-
-
N-[(2S)-1-[[(trans-4-carbamimidamidocyclohexyl)methyl]amino]-4-[3-(carbamimidamidomethyl)cyclohexa-1,5-dien-1-yl]-1-oxobutan-2-yl]-N2-(phenylacetyl)-L-lysinamide
-
-
N-[(2S)-1-[[(trans-4-carbamimidamidocyclohexyl)methyl]amino]-4-[4-(carbamimidamidomethyl)phenyl]-1-oxobutan-2-yl]-N2-(phenylacetyl)-L-lysinamide
-
-
N-[(2S)-4-[3-(aminomethyl)phenyl]-1-[[(trans-4-carbamimidamidocyclohexyl)methyl]amino]-1-oxobutan-2-yl]-N2-(phenylacetyl)-L-lysinamide
-
-
N-[(2S)-4-[4-(aminomethyl)phenyl]-1-[[(trans-4-carbamimidamidocyclohexyl)methyl]amino]-1-oxobutan-2-yl]-N2-(phenylacetyl)-L-ornithinamide
-
-
N-[(2S)-6-amino-1-([(2S)-6-amino-1-[(3R)-3-(carbamimidamidomethyl)pyrrolidin-1-yl]-1-oxohexan-2-yl]amino)-1-oxohexan-2-yl]-2-(biphenyl-4-yl)acetamide
-
-
N-[(2S)-6-amino-1-([(2S)-6-amino-1-[(3S)-3-(carbamimidamidomethyl)pyrrolidin-1-yl]-1-oxohexan-2-yl]amino)-1-oxohexan-2-yl]-2-(biphenyl-4-yl)acetamide
-
-
N-[(2S)-6-amino-1-([(2S)-6-amino-1-[4-(carbamimidamidomethyl)piperidin-1-yl]-1-oxohexan-2-yl]amino)-1-oxohexan-2-yl]-2-(biphenyl-4-yl)acetamide
-
-
N-[(trans-4-carbamimidamidocyclohexyl)methyl]-N2-[(2S)-4-(3-carbamimidamidophenyl)-2-[(phenylacetyl)amino]butanoyl]-L-lysinamide
-
-
N-[(trans-4-carbamimidamidocyclohexyl)methyl]-N2-[(2S)-4-[3-(carbamimidamidomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]-L-lysinamide
-
-
N-[(trans-4-carbamimidamidocyclohexyl)methyl]-N2-[(2S)-4-[4-(carbamimidamidomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]-L-lysinamide
-
-
N2-(1,3-thiazol-2-yl)-L-arginyl-N-[(1S)-2-amino-2-oxo-1-(4-[[4-(trifluoromethyl)benzyl]oxy]phenyl)ethyl]-L-lysinamide
-
-
N2-(4-[(Z)-[3-(cyclohexylmethyl)-2,4-dioxo-1,3-thiazolidin-5-ylidene]methyl]benzoyl)-L-lysyl-N-[(1S)-2-amino-2-oxo-1-phenylethyl]-L-lysinamide
-
-
N2-(biphenyl-4-ylacetyl)-L-lysyl-N-(trans-4-carbamimidamidocyclohexyl)-L-lysinamide
-
-
N2-(biphenyl-4-ylacetyl)-L-lysyl-N-[(2E)-4-carbamimidamidobut-2-en-1-yl]-L-lysinamide
-
-
N2-(biphenyl-4-ylcarbonyl)-L-lysyl-N-(2-carbamimidamidoethyl)-L-lysinamide
-
-
N2-(biphenyl-4-ylcarbonyl)-L-lysyl-N-(3-carbamimidamidopropyl)-L-lysinamide
-
-
N2-(biphenyl-4-ylcarbonyl)-L-lysyl-N-(5-carbamimidamidopentyl)-L-lysinamide
-
-
N2-(phenylacetyl)-L-ornithyl-N-[(trans-4-carbamimidamidocyclohexyl)methyl]-L-lysinamide
-
-
N2-[(2S)-4-[3-(aminomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]-N-[(trans-4-carbamimidamidocyclohexyl)methyl]-L-lysinamide
-
-
N2-[(2S)-4-[4-(aminomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]-N-[(trans-4-carbamimidamidocyclohexyl)methyl]-L-lysinamide
-
-
N2-[(3,4-dichlorophenyl)acetyl]-L-lysyl-N-[(1S)-1-(1-carbamimidoylpiperidin-4-yl)-2-oxoethyl]-L-lysinamide
-
-
N2-[(3,4-dichlorophenyl)acetyl]-L-ornithyl-N-[(trans-4-carbamimidamidocyclohexyl)methyl]-L-lysinamide
-
-
N2-[[4-(carbamimidamidomethyl)phenyl]acetyl]-L-arginyl-3-methyl-L-valyl-N-(4-carbamimidoylbenzyl)-L-argininamide
-
-
N2-[[4-(carbamimidamidomethyl)phenyl]acetyl]-L-arginyl-L-arginyl-N-(4-carbamimidoylbenzyl)-L-argininamide
-
-
N2-[[4-(carbamimidamidomethyl)phenyl]acetyl]-L-arginyl-L-lysyl-N-(4-carbamimidoylbenzyl)-L-argininamide
-
-
N2-[[4-(carbamimidamidomethyl)phenyl]acetyl]-L-arginyl-L-valyl-N-(4-carbamimidoylbenzyl)-L-argininamide
-
-
nona-D-Arg-amide
-
completely inhibits autolysis of the NS2B-NS3pro construct
[2-(2-cyanoethyl)-5-methylpyrazol-3-yl] benzoate
-
105.9% inhibition at 0.05 mM
[4-(2,3-dimethylphenyl)piperazin-1-yl]-(2-ethylsulfonyl-3,4-dihydro-1H-isoquinolin-3-yl)methanone
-
51.6% inhibition at 0.05 mM
[5-amino-1-(4-fluorophenyl)sulfonylpyrazol-3-yl] furan-2-carboxylate
-
107.7% inhibition at 0.05 mM
[5-amino-1-(4-fluorophenyl)sulfonylpyrazol-3-yl] thiophene-2-carboxylate
-
99.1% inhibition at 0.05 mM
[5-amino-1-(4-methoxyphenyl)sulfonylpyrazol-3-yl] 2-bromobenzoate
-
112.5% inhibition at 0.05 mM
[5-amino-1-(4-methoxyphenyl)sulfonylpyrazol-3-yl] benzoate
-
115.6% inhibition at 0.05 mM
[5-amino-1-(4-methoxyphenyl)sulfonylpyrazol-3-yl] furan-2-carboxylate
-
99.3% inhibition at 0.05 mM
[5-amino-1-(4-methoxyphenyl)sulfonylpyrazol-3-yl] thiophene-2-carboxylate
-
116.3% inhibition at 0.05 mM
[5-amino-1-(4-methylphenyl)sulfonylpyrazol-3-yl] furan-2-carboxylate
-
96.6% inhibition at 0.05 mM
[5-amino-1-(4-methylphenyl)sulfonylpyrazol-3-yl] thiophene-2-carboxylate
-
86.8% inhibition at 0.05 mM
Aprotinin
-
non-specific inhibitor of NS2B-NS3pro, full inhibition at 0.001 mM
additional information
-
product inhibition of the protease by the cleaved C-terminus of NS2B. The reaction product Lys-Arg-COO- remains in the P2-P1 site after cleavage and effectively blocks the active site for both cis and trans substrates
-
additional information
-
development of a series of alpha-aminoalkylphosphonate diphenyl esters and their peptidyl derivatives as potent inhibitors of the NS2B/NS3 protease. Inhibitor synthesis and mechanism of serine proteases inhibition by alpha-aminoalkylphosphonate diphenyl esters involving the oxyanion hole, overview. Molecular docking
-
additional information
-
discovery, X-ray crystallography and antiviral activity of allosteric inhibitors of flavivirus NS2B-NS3 protease. Compound screening followed by medicinal chemistry yield a series of drug-like, broadly active inhibitors of flavivirus proteases with IC50 as low as 120 nM. The inhibitors exhibit significant antiviral activities in cells (EC68: 300-600 nM). X-ray studies reveal that the inhibitors bind to an allosteric, mostly hydrophobic pocket of dengue NS3 and hold the protease in an open, catalytically inactive conformation
-
additional information
-
inhibitor screening, a strong inhibitory potency is found for simple phenylacetyl-capped tripeptides containing a C-terminal P1 arginyl amide moiety and for their elongated derivatives with one or two glycine residues in the P1' and P2' positions. The compounds seem to be poor substrates of the WNV NS2BNS3 protease and therefore, act as competitive inhibitors. Inhibitory potencies of synthesized compounds, comparison to human furin, and West nile virus, structure-activity relationships, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
formation of an active protease does not require neither cleavage of NS2B from NS3 nor a free NS3 N-terminus
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.004
butyloxycarbonyl-Arg-Val-Arg-Arg-7-amido-4-methylcoumarin
mutant G22S
0.03
butyloxycarbonyl-Arg-Val-Arg-Arg-7-amido-4-methylcoumarin
wild-type
0.004
pyroglutamic acid-Arg-Thr-Lys-Arg-7-amido-4-methylcoumarin
mutant G22S
0.03
pyroglutamic acid-Arg-Thr-Lys-Arg-7-amido-4-methylcoumarin
wild-type
0.0013
L-pGlu-L-Arg-L-Thr-L-Lys-L-Arg-7-amido-4-methylcoumarin
-
mutant enzyme T52V, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
0.0588
L-pGlu-L-Arg-L-Thr-L-Lys-L-Arg-7-amido-4-methylcoumarin
-
mutant enzyme K48A, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
0.071
L-pGlu-L-Arg-L-Thr-L-Lys-L-Arg-7-amido-4-methylcoumarin
-
wild type enzyme, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
0.089
L-pGlu-L-Arg-L-Thr-L-Lys-L-Arg-7-amido-4-methylcoumarin
-
mutant enzyme R76L, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
0.059
pyroglutamic acid-Arg-Thr-Lys-Arg-7-amido-4-methylcoumarin
-
mutant K48A
0.036
t-butoxycarbonyl-Arg-Val-Arg-Arg-7-amido-4-methylcoumarin
-
mutant K48A
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.013
L-pGlu-L-Arg-L-Thr-L-Lys-L-Arg-7-amido-4-methylcoumarin
-
mutant enzyme T52V, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
5.25
L-pGlu-L-Arg-L-Thr-L-Lys-L-Arg-7-amido-4-methylcoumarin
-
mutant enzyme K48A, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
6.3
L-pGlu-L-Arg-L-Thr-L-Lys-L-Arg-7-amido-4-methylcoumarin
-
wild type enzyme, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
7.3
L-pGlu-L-Arg-L-Thr-L-Lys-L-Arg-7-amido-4-methylcoumarin
-
mutant enzyme R76L, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
82
L-pGlu-L-Arg-L-Thr-L-Lys-L-Arg-7-amido-4-methylcoumarin
-
mutant enzyme R76L, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
88
L-pGlu-L-Arg-L-Thr-L-Lys-L-Arg-7-amido-4-methylcoumarin
-
wild type enzyme, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
89.3
L-pGlu-L-Arg-L-Thr-L-Lys-L-Arg-7-amido-4-methylcoumarin
-
mutant enzyme K48A, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
100
L-pGlu-L-Arg-L-Thr-L-Lys-L-Arg-7-amido-4-methylcoumarin
-
mutant enzyme T52V, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0442
(2S)-4-[3-(aminomethyl)phenyl]-2-([(2S)-4-[3-(aminomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]amino)-N-[(trans-4-carbamimidamidocyclohexyl)methyl]butanamide
-
pH 8.5, 22°C
0.0136
(2S)-4-[4-(aminomethyl)phenyl]-2-([(2S)-4-[4-(aminomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]amino)-N-[(trans-4-carbamimidamidocyclohexyl)methyl]butanamide
-
pH 8.5, 22°C
0.0216
(2S)-N-[(trans-4-carbamimidamidocyclohexyl)methyl]-4-[3-(carbamimidamidomethyl)phenyl]-2-([(2S)-4-[3-(carbamimidamidomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]amino)butanamide
-
pH 8.5, 22°C
0.0853
(2S)-N-[(trans-4-carbamimidamidocyclohexyl)methyl]-4-[4-(carbamimidamidomethyl)phenyl]-2-([(2S)-4-[4-(carbamimidamidomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]amino)butanamide
-
pH 8.5, 22°C
0.000264
antibody D05320
-
wild type enzyme, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
-
0.0004
antibody D05321
-
wild type enzyme, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
-
0.00017
antibody D05322
-
wild type enzyme, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
-
0.000031
antibody D05323
-
wild type enzyme, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
-
0.000058
antibody D05444
-
wild type enzyme, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
-
0.000035
antibody D05445
-
wild type enzyme, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
-
0.000288
antibody D05446
-
wild type enzyme, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
-
0.013
diphenyl (1-[[(benzyloxy)carbonyl]amino]-3-carbamimidamidopropyl)phosphonate
-
pH 8.5, 37°C
0.022
diphenyl (5-amino-1-[[(benzyloxy)carbonyl]amino]pentyl)phosphonate
-
pH 8.5, 37°C
0.01
diphenyl [[[(benzyloxy)carbonyl]amino](4-carbamimidamidophenyl)methyl]phosphonate
-
pH 8.5, 37°C
0.004
diphenyl [[[(benzyloxy)carbonyl]amino](carbamimidamido)methyl]phosphonate
-
pH 8.5, 37°C
0.0182
N-[(2S)-1-[[(trans-4-carbamimidamidocyclohexyl)methyl]amino]-4-(4-carbamimidamidophenyl)-1-oxobutan-2-yl]-N2-(phenylacetyl)-L-lysinamide
-
pH 8.5, 22°C
0.0994
N-[(2S)-1-[[(trans-4-carbamimidamidocyclohexyl)methyl]amino]-4-[3-(carbamimidamidomethyl)cyclohexa-1,5-dien-1-yl]-1-oxobutan-2-yl]-N2-(phenylacetyl)-L-lysinamide
-
pH 8.5, 22°C
0.0756
N-[(2S)-1-[[(trans-4-carbamimidamidocyclohexyl)methyl]amino]-4-[4-(carbamimidamidomethyl)phenyl]-1-oxobutan-2-yl]-N2-(phenylacetyl)-L-lysinamide
-
pH 8.5, 22°C
0.134
N-[(2S)-4-[3-(aminomethyl)phenyl]-1-[[(trans-4-carbamimidamidocyclohexyl)methyl]amino]-1-oxobutan-2-yl]-N2-(phenylacetyl)-L-lysinamide
-
pH 8.5, 22°C
0.0289
N-[(2S)-4-[4-(aminomethyl)phenyl]-1-[[(trans-4-carbamimidamidocyclohexyl)methyl]amino]-1-oxobutan-2-yl]-N2-(phenylacetyl)-L-ornithinamide
-
pH 8.5, 22°C
0.0298
N-[(trans-4-carbamimidamidocyclohexyl)methyl]-N2-[(2S)-4-(3-carbamimidamidophenyl)-2-[(phenylacetyl)amino]butanoyl]-L-lysinamide
-
pH 8.5, 22°C
0.0296
N-[(trans-4-carbamimidamidocyclohexyl)methyl]-N2-[(2S)-4-[3-(carbamimidamidomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]-L-lysinamide
-
pH 8.5, 22°C
0.044
N-[(trans-4-carbamimidamidocyclohexyl)methyl]-N2-[(2S)-4-[4-(carbamimidamidomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]-L-lysinamide
-
pH 8.5, 22°C
0.000039
N2-(1,3-thiazol-2-yl)-L-arginyl-N-[(1S)-2-amino-2-oxo-1-(4-[[4-(trifluoromethyl)benzyl]oxy]phenyl)ethyl]-L-lysinamide
-
pH 8.5, 37°C
0.00075
N2-(4-[(Z)-[3-(cyclohexylmethyl)-2,4-dioxo-1,3-thiazolidin-5-ylidene]methyl]benzoyl)-L-lysyl-N-[(1S)-2-amino-2-oxo-1-phenylethyl]-L-lysinamide
-
pH 8.5, 37°C
0.000006
N2-(biphenyl-4-ylacetyl)-L-lysyl-L-Lys-L-Arg-aldehyde
-
pH 8.5, 37°C
0.00156
N2-(phenylacetyl)-L-lysyl-N-(2-aminoprop-2-en-1-yl)-L-lysinamide
-
pH 8.5, 22°C
0.015
N2-(phenylacetyl)-L-lysyl-N-(4-amino-4-oxobutyl)-L-lysinamide
-
pH 8.5, 22°C
0.017
N2-(phenylacetyl)-L-lysyl-N-(5-amino-5-oxopentyl)-L-lysinamide
-
pH 8.5, 22°C
0.0012
N2-(phenylacetyl)-L-ornithyl-N-[(trans-4-carbamimidamidocyclohexyl)methyl]-L-lysinamide
-
pH 8.5, 22°C
0.0222
N2-[(2S)-4-[3-(aminomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]-N-[(trans-4-carbamimidamidocyclohexyl)methyl]-L-lysinamide
-
pH 8.5, 22°C
0.00471
N2-[(2S)-4-[4-(aminomethyl)phenyl]-2-[(phenylacetyl)amino]butanoyl]-N-[(trans-4-carbamimidamidocyclohexyl)methyl]-L-lysinamide
-
pH 8.5, 22°C
0.00013
N2-[(3,4-dichlorophenyl)acetyl]-L-lysyl-N-[(1S)-1-(1-carbamimidoylpiperidin-4-yl)-2-oxoethyl]-L-lysinamide
-
pH 8.5, 37°C
0.00011
N2-[(3,4-dichlorophenyl)acetyl]-L-ornithyl-N-[(trans-4-carbamimidamidocyclohexyl)methyl]-L-lysinamide
-
pH 8.5, 22°C
0.0018
N2-[(3,4-dimethylphenyl)acetyl]-L-lysyl-L-lysylglycinamide
-
pH 8.5, 22°C
0.00036
N2-[[3-(aminomethyl)phenyl]acetyl]-L-lysyl-L-lysinamide
-
pH 8.5, 22°C
0.00018
N2-[[3-(carbamimidamidomethyl)phenyl]acetyl]-L-lysyl-L-lysinamide
-
pH 8.5, 22°C
0.00038
N2-[[4-(aminomethyl)phenyl]acetyl]-L-lysyl-L-lysinamide
-
pH 8.5, 22°C
0.00645
N2-[[4-(carbamimidamidomethyl)phenyl]acetyl]-L-arginyl-3-methyl-L-valyl-N-(4-carbamimidoylbenzyl)-L-argininamide
-
pH 8.5, 22°C
0.00065
N2-[[4-(carbamimidamidomethyl)phenyl]acetyl]-L-arginyl-L-arginyl-N-(4-carbamimidoylbenzyl)-L-argininamide
-
pH 8.5, 22°C
0.00082
N2-[[4-(carbamimidamidomethyl)phenyl]acetyl]-L-arginyl-L-lysyl-N-(4-carbamimidoylbenzyl)-L-argininamide
-
pH 8.5, 22°C
0.0057
N2-[[4-(carbamimidamidomethyl)phenyl]acetyl]-L-arginyl-L-valyl-N-(4-carbamimidoylbenzyl)-L-argininamide
-
pH 8.5, 22°C
0.00011
N2-[[4-(carbamimidamidomethyl)phenyl]acetyl]-L-lysyl-L-lysinamide
-
pH 8.5, 22°C
0.00002
Aprotinin
-
wild type enzyme, in 20 mM Tris/HCl buffer, pH 8.0, at 22°C
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.1
1-(2,6-difluorophenyl)-2-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-yl]ethanol
West Nile virus
-
IC50 above 0.1 mM, in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.0239
1-(2,6-difluorophenyl)-2-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-yl]ethanone
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.0388
1-(2-fluorophenyl)-2-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-yl]ethanone
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.00926
1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-yl 2,6-difluoro-3-methylbenzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.00871
1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-yl 2,6-difluorobenzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.00403
1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-yl benzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.00943
1-benzyl-3-methyl-1H-pyrazol-5-yl 2,6-difluoro-3-methylbenzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.00804
1-benzyl-3-methyl-1H-pyrazol-5-yl 2,6-difluorobenzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.1
2-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-yl]-1-phenylethanol
West Nile virus
-
IC50 above 0.1 mM, in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.1
2-[1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-5-yl]-1-phenylethanone
West Nile virus
-
IC50 above 0.1 mM, in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.01192
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,3,4-trifluorobenzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.01069
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,3,5,6-tetrafluoro-4-methylbenzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.00097
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,3,6-trifluorobenzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.02618
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,4,5-trifluorobenzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.00183
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,4,6-trifluorobenzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.00196
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,4-difluorobenzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.0049
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,5-difluorobenzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.1
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,6-dichlorobenzoate
West Nile virus
-
IC50 above 0.1 mM, in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.00428
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,6-difluoro-3-methylbenzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.00031
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2,6-difluorobenzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.1
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2-ethoxybenzoate
West Nile virus
-
IC50 above 0.1 mM, in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.04549
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2-fluoro-3-(trifluoromethyl)benzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.00355
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2-methylbenzoate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.1
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 2-nitrobenzoate
West Nile virus
-
IC50 above 0.1 mM, in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.00122
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl 3-chlorothiophene-2-carboxylate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.005
5-amino-1-[(4-methoxyphenyl)sulfonyl]-1H-pyrazol-3-yl thiophene-3-carboxylate
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.0138
5-[(E)-2-(2,6-difluorophenyl)ethenyl]-1-(4-methoxybenzyl)-3-methyl-1H-pyrazole
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.04771
N-(9-ethylcarbazol-3-yl)-2-[(4-ethyl-5-furan-2-yl-1,2,4-triazol-3-yl)sulfanyl]acetamide
West Nile virus
-
-
0.1
N-[(2S)-6-amino-1-([(2S)-6-amino-1-[(3R)-3-(carbamimidamidomethyl)pyrrolidin-1-yl]-1-oxohexan-2-yl]amino)-1-oxohexan-2-yl]-2-(biphenyl-4-yl)acetamide
West Nile virus
-
pH 8.0, 37°C, value above
0.02
N-[(2S)-6-amino-1-([(2S)-6-amino-1-[(3S)-3-(carbamimidamidomethyl)pyrrolidin-1-yl]-1-oxohexan-2-yl]amino)-1-oxohexan-2-yl]-2-(biphenyl-4-yl)acetamide
West Nile virus
-
pH 8.0, 37°C
0.1
N-[(2S)-6-amino-1-([(2S)-6-amino-1-[4-(carbamimidamidomethyl)piperidin-1-yl]-1-oxohexan-2-yl]amino)-1-oxohexan-2-yl]-2-(biphenyl-4-yl)acetamide
West Nile virus
-
pH 8.0, 37°C, value above
0.0047
N2-(biphenyl-4-ylacetyl)-L-lysyl-N-(4-carbamimidamidobutyl)-L-lysinamide
West Nile virus
-
pH 8.0, 37°C
0.1
N2-(biphenyl-4-ylacetyl)-L-lysyl-N-(trans-4-carbamimidamidocyclohexyl)-L-lysinamide
West Nile virus
-
pH 8.0, 37°C, value above
0.0612
N2-(biphenyl-4-ylacetyl)-L-lysyl-N-[(2E)-4-carbamimidamidobut-2-en-1-yl]-L-lysinamide
West Nile virus
-
pH 8.0, 37°C
0.1
N2-(biphenyl-4-ylcarbonyl)-L-lysyl-N-(2-carbamimidamidoethyl)-L-lysinamide
West Nile virus
-
pH 8.0, 37°C, value above
0.1
N2-(biphenyl-4-ylcarbonyl)-L-lysyl-N-(3-carbamimidamidopropyl)-L-lysinamide
West Nile virus
-
pH 8.0, 37°C, value above
0.1
N2-(biphenyl-4-ylcarbonyl)-L-lysyl-N-(5-carbamimidamidopentyl)-L-lysinamide
West Nile virus
-
pH 8.0, 37°C, value above
0.0182
N2-acetyl-L-lysyl-N-(4-carbamimidamidobutyl)-L-lysinamide
West Nile virus
-
pH 8.0, 37°C
0.001353
SID-3717586
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.00011
SID-4245669
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.000105
SID-852843
West Nile virus
-
in 10 mM Tris-HCl buffer, pH 8.0, containing 20% (v/v) glycerol and 0.005% Brij 35
0.03857
[4-(2,3-dimethylphenyl)piperazin-1-yl]-(2-ethylsulfonyl-3,4-dihydro-1H-isoquinolin-3-yl)methanone
West Nile virus
-
-
0.001161
[5-amino-1-(4-fluorophenyl)sulfonylpyrazol-3-yl] thiophene-2-carboxylate
West Nile virus
-
-
0.001651
[5-amino-1-(4-fluorophenyl)sulfonylpyrazol-3-yl]furan-2-carboxylate
West Nile virus
-
-
0.000297
[5-amino-1-(4-methoxyphenyl)sulfonylpyrazol-3-yl] 2-bromobenzoate
West Nile virus
-
-
0.000553
[5-amino-1-(4-methoxyphenyl)sulfonylpyrazol-3-yl] furan-2-carboxylate
West Nile virus
-
-
0.00011
[5-amino-1-(4-methoxyphenyl)sulfonylpyrazol-3-yl] thiophene-2-carboxylate
West Nile virus
-
-
0.01439
[5-amino-1-(4-methylphenyl)sulfonylpyrazol-3-yl] furan-2-carboxylate
West Nile virus
-
-
0.002405
[5-amino-1-(4-methylphenyl)sulfonylpyrazol-3-yl] thiophene-2-carboxylate
West Nile virus
-
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
the flavivirus NS3 protein is associated with the endoplasmic reticulum membrane via its close interaction with the central hydrophilic region of the NS2B integral membrane protein
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
the N-terminal region of NS3 and its cofactor NS2B constitute the protease that cleaves the viral polyprotein. The NS3 C-terminal domain possesses RNA helicase, nucleoside and RNA triphosphatase activities and is involved both in viral RNA replication and virus particle formation. NS2B-NS3 protein plays multiple roles in the virus life cycle. NS2B-NS3 serves as a hub for the assembly of the flavivirus replication complex and also modulates viral pathogenesis and the host immune response
evolution
-
the flavivirus NS2B-NS3 protease is highly conserved in Zika, West Nile, and Dengue viruses
additional information
enzyme ligand binding structure analysis, three-dimensional enzyme structure analysis
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). POLG_WNV
3430
20
380110
Swiss-Prot
other Location (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
analysis of enzyme structures, PDB IDs 2YOL, 3E90, 2FP7, 2IJO, and 2GGV
NS2B-NS3 complex complexed with benzoyl-Nle-Lys-Thr-Arg-H, and trypsin digested NS2B-NS3 complex
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D42G
has no dramatic effect on either the catalytic activity (50% of wild-type) or self-proteolysis of NS2B-NS3pro. Aprotinin efficiently inhibits proteolytic activity
G22S
resistant to autoproteolysis at the flexible linker region, retains 3% residual activity
K48A
resistant to autoproteolysis at the flexible linker region. Aprotinin efficiently inhibits proteolytic activity
G460L
-
no autolytic cleavage, but is an efficient enzyme against the artificial substrate CFP-LQYTKRGGVLWD-YFP
H51A
K48A
P131K/T132P
-
decrease in kcat, which is partially compensated by an improvement in the substrate binding. Shift of the cleavage preferences toward that of the Dengue virus proteinase
R76L
S135A
T52V
additional information
H51A
-
devoid of any proteolytic activity and incapable of autolytically cleaving either the NS2B sequence or the NS3pro-hel boundary. Resistant to the proteolysis in trans by the external, highly active NS2B-NS3pro construct
K48A
-
is a single-chain protein and fully resistant to autolysis at the linker region, exhibits high stability and functional activity, cleaves pyroglutamic acid-Arg-Thr-Lys-Arg-7-amino-4-methylcoumarin
K48A
-
mutation of the C-terminal amino acid residue of the NS2B sequence, inactivates the autolytic cleavage site. Does not have any significant effect on the catalytic activity. Readily cleaved in cis by the integral NS2B-NS3pro activity
K48A
-
the mutant displays slightly increased catalytic efficiency compared to the wild type enzyme
R76L
-
kinetic parameters are similar to those of the wild-type. Shift of the cleavage preferences toward that of the Dengue virus proteinase
R76L
-
the mutant displays reduced catalytic efficiency compared to the wild type enzyme
T52V
-
exhibits a significant loss of kcat, which is compensated by an improvement in substrate binding. Does not cause any significant differences in the cleavage subsite specificity. Cleavage preferences of the T52V mutant construct are similar to those of the original West Nile virus proteinase
T52V
-
the mutant displays increased catalytic efficiency compared to the wild type enzyme
additional information
D(32)DD(34) substitution for AAA inactivates NS2B-NS3pro, retains 1% residual activity
additional information
-
D(32)DD(34) substitution for AAA inactivates NS2B-NS3pro, retains 1% residual activity
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
NS2B-NS3pro construct purified by Co2+-chelating Sepharose Fast Flow chromatography
NS2B-NS3pro wild-type and K48A constructs purified by Co2+ affinity chromatography and gel filtration, to homogeneity
-
wild-type and mutant NS2B-NS3pro and NS2B-NS3prohel constructs, C-terminally tagged with a hexahistidine tag, purified by Co2+ affinity chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
NS2B-NS3pro construct cloned into the pET101/D-TOPO vector C-terminally tagged with the His x 6 tag and expressed in Escherichia coli BL21(DE3) Codon Plus cells
into the pET101 and expressed in Escherichia coli BL21(DE3) Codon Plus cells
-
mutant K48A cloned into pET101/D-TOPO vector and expressed in Escherichia coli BL21(DE3) Codon Plus cells
-
NS2B-NS3pro wild-type and K48A constructs cloned into pET101 vector and expressed in Escherichia coli BL21 (DE3) Codon Plus cells
-
wild-type Dengue virus and West Nile virus NS2B-NS3pro, together with West Nile virus/Dengue virus chimeras expressed with C-terminal His tags in Escherichia coli BL21(DE3) Codon Plus cells
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
analysis
-
NS2B-NS3pro K48A mutant construct is well suited for follow-up purification and structural and drug design studies
drug development
molecular biology
-
it is demonstrated that the WNV NS2B/NS3pro-hel is an active endoproteolytic enzyme at the ER membrane and the in-cell selectivity profiling of the membrane-anchored flaviviral protease is reported
drug development
useful for the development of specific allosteric inhibitors designed to interfere with the productive interactions of NS2B with NS3pro
drug development
flavivirus NS2B-NS3 protease-helicase is a target for antiviral drug development
drug development
-
switched cleavage preferences of West Nile virus NS2B-NS3(pro)teinase may provide valuable data for the design of optimized substrates and substrate-based selective inhibitors of flaviviral proteinases
drug development
-
unique cleavage preferences of the West Nile virus protease promise novelty for the design of potent inhibitors that may be selective for the flaviviral proteases over proteases of the host cell and thus provide a solid base for follow-on structural and functional studies
drug development
-
the viral serine protease NS2B/NS3 is an attractive target for the development of anti-WNV agents
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
D'Arcy, A.; Chaillet, M.; Schiering, N.; Villard, F.; Lim, S.P.; Lefeuvre, P.; Erbel, P.
Purification and crystallization of dengue and West Nile virus NS2B-NS3 complexes
Acta Crystallogr. Sect. F
62
157-162
2006
Dengue virus, West Nile virus
Ramanathan, M.P.; Chambers, J.A.; Pankhong, P.; Chattergoon, M.; Attatippaholkun, W.; Dang, K.; Shah, N.; Weiner, D.B.
Host cell killing by the West Nile Virus NS2B-NS3 proteolytic complex: NS3 alone is sufficient to recruit caspase-8-based apoptotic pathway
Virology
345
56-72
2006
West Nile virus
Johnston, P.A.; Phillips, J.; Shun, T.Y.; Shinde, S.; Lazo, J.S.; Huryn, D.M.; Myers, M.C.; Ratnikov, B.I.; Smith, J.W.; Su, Y.; Dahl, R.; Cosford, N.D.; Shiryaev, S.A.; Strongin, A.Y.
HTS identifies novel and specific uncompetitive inhibitors of the two-component NS2B-NS3 proteinase of West Nile virus
Assay Drug Dev. Technol.
5
737-750
2007
West Nile virus
Shiryaev, S.A.; Kozlov, I.A.; Ratnikov, B.I.; Smith, J.W.; Lebl, M.; Strongin, A.Y.
Cleavage preference distinguishes the two-component NS2B-NS3 serine proteinases of Dengue and West Nile viruses
Biochem. J.
401
743-752
2007
West Nile virus, Dengue virus type 2, Dengue virus type 2 16681, West Nile virus NY99
Bera, A.K.; Kuhn, R.J.; Smith, J.L.
Functional characterization of cis and trans activity of the Flavivirus NS2B-NS3 protease
J. Biol. Chem.
282
12883-12892
2007
Japanese encephalitis virus, West Nile virus, Yellow fever virus, Dengue virus type 2, Dengue virus type 4, West Nile virus NY99
Radichev, I.; Shiryaev, S.A.; Aleshin, A.E.; Ratnikov, B.I.; Smith, J.W.; Liddington, R.C.; Strongin, A.Y.
Structure-based mutagenesis identifies important novel determinants of the NS2B cofactor of the West Nile virus two-component NS2B-NS3 proteinase
J. Gen. Virol.
89
636-641
2008
West Nile virus (P06935), West Nile virus, West Nile virus NY99 (P06935)
Shiryaev, S.A.; Ratnikov, B.I.; Aleshin, A.E.; Kozlov, I.A.; Nelson, N.A.; Lebl, M.; Smith, J.W.; Liddington, R.C.; Strongin, A.Y.
Switching the substrate specificity of the two-component NS2B-NS3 flavivirus proteinase by structure-based mutagenesis
J. Virol.
81
4501-4509
2007
Dengue virus, West Nile virus
Shiryaev, S.A.; Aleshin, A.E.; Ratnikov, B.I.; Smith, J.W.; Liddington, R.C.; Strongin, A.Y.
Expression and purification of a two-component flaviviral proteinase resistant to autocleavage at the NS2B-NS3 junction region
Protein Expr. Purif.
52
334-339
2007
West Nile virus
Shiryaev, S.A.; Radichev, I.A.; Ratnikov, B.I.; Aleshin, A.E.; Gawlik, K.; Stec, B.; Frisch, C.; Knappik, A.; Strongin, A.Y.
Isolation and characterization of selective and potent human Fab inhibitors directed to the active-site region of the two-component NS2B-NS3 proteinase of West Nile virus
Biochem. J.
427
369-376
2010
West Nile virus, West Nile virus NY99
Sidique, S.; Shiryaev, S.A.; Ratnikov, B.I.; Herath, A.; Su, Y.; Strongin, A.Y.; Cosford, N.D.
Structure-activity relationship and improved hydrolytic stability of pyrazole derivatives that are allosteric inhibitors of West Nile Virus NS2B-NS3 proteinase
Bioorg. Med. Chem. Lett.
19
5773-5777
2009
West Nile virus
Schueller, A.; Yin, Z.; Brian Chia, C.S.; Doan, D.N.; Kim, H.K.; Shang, L.; Loh, T.P.; Hill, J.; Vasudevan, S.G.
Tripeptide inhibitors of dengue and West Nile virus NS2B-NS3 protease
Antiviral Res.
92
96-101
2011
Dengue virus, West Nile virus
Condotta, S.A.; Martin, M.M.; Boutin, M.; Jean, F.
Detection and in-cell selectivity profiling of the full-length West Nile virus NS2B/NS3 serine protease using membrane-anchored fluorescent substrates
Biol. Chem.
391
549-559
2010
West Nile virus
Lim, H.A.; Joy, J.; Hill, J.; San Brian Chia, C.
Novel agmatine and agmatine-like peptidomimetic inhibitors of the West Nile virus NS2B/NS3 serine protease
Eur. J. Med. Chem.
46
3130-3134
2011
West Nile virus
Ang, M.J.; Li, Z.; Lim, H.A.; Ng, F.M.; Then, S.W.; Wee, J.L.; Joy, J.; Hill, J.; Chia, C.S.
A P2 and P3 substrate specificity comparison between the Murray Valley encephalitis and West Nile virus NS2B/NS3 protease using C-terminal agmatine dipeptides
Peptides
52
49-52
2014
West Nile virus, Murray Valley encephalitis virus
Luo, D.; Vasudevan, S.G.; Lescar, J.
The flavivirus NS2B-NS3 protease-helicase as a target for antiviral drug development
Antiviral Res.
118
148-158
2015
Yellow fever virus (P03314), Murray Valley encephalitis virus (P05769), West Nile virus (P06935), Kunjin virus (P14335), dengue virus type I (P17763), Japanese encephalitis virus (P27395), Dengue virus type 2 (P29990), Dengue virus type 4 (Q2YHF0), Kokobera virus (Q32ZD5), Dengue virus type 3 (Q6YMS3), Dengue virus type 2 Thailand/16681/1984 (P29990), Dengue virus type 3 Martinique/1243/1999 (Q6YMS3), Yellow fever virus 17D vaccine (P03314), Dengue virus type 4 Thailand/0348/1991 (Q2YHF0), dengue virus type I Nauru/West Pac/1974 (P17763), Japanese encephalitis virus SA-14 (P27395), Kunjin virus MRM61C (P14335), Murray Valley encephalitis virus MVE-1-51 (P05769)
Yao, Y.; Huo, T.; Lin, Y.L.; Nie, S.; Wu, F.; Hua, Y.; Wu, J.; Kneubehl, A.R.; Vogt, M.B.; Rico-Hesse, R.; Song, Y.
Discovery, X-ray crystallography and antiviral activity of allosteric inhibitors of flavivirus NS2B-NS3 protease
J. Am. Chem. Soc.
141
6832-6836
2019
Dengue virus, West Nile virus, Zika virus
Kouretova, J.; Hammamy, M.Z.; Epp, A.; Hardes, K.; Kallis, S.; Zhang, L.; Hilgenfeld, R.; Bartenschlager, R.; Steinmetzer, T.
Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication
J. Enzyme Inhib. Med. Chem.
32
712-721
2017
Dengue virus, West Nile virus
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