3.4.21.98: hepacivirin

This is an abbreviated version!
For detailed information about hepacivirin, go to the full flat file.

Reaction

Hydrolysis of four peptide bonds in the viral precursor polyprotein, commonly with Asp or Glu in the P6 position, Cys or Thr in P1 and Ser or Ala in P1' =

Synonyms

Cpro-2, Cpro-2 proteinase, Den2 protease, HCV NS3, HCV NS3 protease, HCV NS3/4A, HCV NS3/4A protease, Hepacivirin, hepatitis C virus NS3 serine protease, hepatitis C virus NS3/4A protease, non-structural 3 protein, nonstructural 3 protease, nonstructural protein 3, nonstructural protein 3-4A serine protease, nonstructural protein 3-4Agene, nonstructural protein 3/4A protease, NS2/3 protease, NS2B-NS3 proteinase, NS2B/NS3 protease, NS3, NS3 protease, NS3 protein, NS3 proteinase, NS3 serine protease, NS3 serine proteinase, NS3-4A, NS3-4A protease, NS3-4A serine protease, NS3-4A serine protease complex, NS3-4A serine proteinase, NS3-NS4A protease, NS3-protease, NS3-SP, NS3/4a, NS3/4A protease, NS3/4A protease complex, NS3/4A serine protease, NS34Agene, NS3?4A, NS5A-5B protease, P70, polyprotein-processing proteinase NS3, proteinase NS3, proteinase, polyprotein-processing, NS3, sc-protease, serine protease NS3, serine proteinase NS3

ECTree

     3 Hydrolases

         3.4 Acting on peptide bonds (peptidases)

             3.4.21 Serine endopeptidases

                3.4.21.98 hepacivirin

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Results	in table
19	Activating Compound
54	AA Sequence
37	Application
1	CAS Registry Number
41	Cloned(Commentary)
19	Cofactor
19	Crystallization (Commentary)
17	General Information
1	General Stability
266	IC50 Value
948	Inhibitors
7	kcat/KM [mM/s]
565	Ki Value [mM]
146	KM Value [mM]
2	Localization
6	Metals/Ions
13	Molecular Weight [Da]
10	Natural Substrates/ Products (Substrates)
158	Organism
157	PDB ID
9	pH Optimum
3	pH Stability
1	Posttranslational Modification
273	Protein Variants
26	Purification (Commentary)
1	Reaction
1	Reaction Type
145	Reference
2	Source Tissue
2	Specific Activity [micromol/min/mg]
4	Storage Stability
146	Substrates and Products (Substrate)
9	Subunits
158	Synonyms
4	Temperature Optimum [°C]
3	Temperature Stability [°C]
140	Turnover Number [1/s]

Application

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Application on EC 3.4.21.98 - hepacivirin

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APPLICATION

ORGANISM

UNIPROT

COMMENTARY

LITERATURE

analysis

Hepacivirus C

-

generation of NS3/4A/Lap/LC-1 triple transgenic mouse liver-specifically and conditionally expressing reporter luciferase Fluc, Cre recombinase and reverse tetracycline-controlled transcriptional activator. NS3/4A protein is strictly and conditionally expressed in the liver of doxycycline-induced triple transgenic mice

732489

drug development

22 entries

medicine

9 entries

molecular biology

Hepacivirus C

-

in order to develop an efficient screening method to identify viral proteins and their ability to block Jak-Stat signaling, the 2FTGH (human fibrosarcoma cells) cell assay system is used in combination with transient transfection of hepatitis C virus proteins: Using 1000 U/ml interferon and 30 mM 6-thioguanine to treat 2FTGH cells, it is established that transient protein expression in this cell system yields 39% and 0% cell survival for the positive (HPV E7) and negative controls (GFP expression) respectively. Transient expression of HCV Core-p7 results in 22% cell survival, consistent with previous reports, while expression of the HCV serine protease NS3/4a results in 54% cell survival. Furthermore, it is shown that NS3/4a inhibits phosphorylation of Stat-1 at the serine residue

695646

pharmacology

Hepacivirus C

-

the viral protease may be a target for antiviral drugs

81439

additional information

3 entries

drug development

Yellow fever virus

-

characteristics of Yellow fever virus protease are very similar to those reported for dengue and West Nile virus proteases, and suggest that pan-flavivirus NS3 protease drugs may be developed for flaviviral diseases

681172

drug development

Hepacivirus C

-

[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 is a lead for future SAR development

685533

drug development

Hepacivirus C

-

barrier state B1 is a relevant molecular structure to be considered in the design of new inhibitors of the NS3 enzyme. Residues Arg-109, Lys-136, Gly-137, Arg-155 and Asp-79 are responsible for the electrostatic stabilization of B1. The tetra-coordinated intermediate I1, may also be of interest as possible targets for the design of new drugs

695029

drug development

Hepacivirus C

-

combination with IFN-alpha with or without ribavirin may be a potential therapeutic strategy to suppress the emergence of Hepatitis C virus variants with substitutions at NS3 protease residue 155

692999

drug development

Hepacivirus C

-

correct binding mode of 2-O-(4-O-galloylgalloyl)-1,3,4-tri-O-galloyl-beta-D-glucose can be used as a novel scaffold for anti-hepatitis C virus for the further reconstruction and design of new protease inhibitors

685513

drug development

Hepacivirus C

-

design of epitope-based vaccines, where epitopes preferably should be those in which the virus is unable to mutate due to viral fitness

681224

drug development

Hepacivirus C

A8DX91, A8DXI7, A8DXT5, B0L492, B0L493, B0L494, B0L495, B0L496, B0L497, Q8JRC7

genotype 1a, different catalytic efficiencies among NS3/4A proteases from different or similar hepatitis C virus genotypes. Because modulation of enzymatic activity of the protease is dependent on the interactions of a small number of NS4A amino acid residues, the design of small peptidomimetic protease inhibitors may be feasible

695259

drug development

Hepacivirus C

A8DX91, A8DXI7, A8DXT5, B0L492, B0L493, B0L494, B0L495, B0L496, B0L497, Q8JRC7

genotype 1b, different catalytic efficiencies among NS3/4A proteases from different or similar hepatitis C virus genotypes. Because modulation of enzymatic activity of the protease is dependent on the interactions of a small number of NS4A amino acid residues, the design of small peptidomimetic protease inhibitors may be feasible

695259

drug development

Hepacivirus C

A8DX91, A8DXI7, A8DXT5, B0L492, B0L493, B0L494, B0L495, B0L496, B0L497, Q8JRC7

genotype 3a, different catalytic efficiencies among NS3/4A proteases from different or similar hepatitis C virus genotypes. Because modulation of enzymatic activity of the protease is dependent on the interactions of a small number of NS4A amino acid residues, the design of small peptidomimetic protease inhibitors may be feasible

695259

drug development

Hepacivirus C

A8DX91, A8DXI7, A8DXT5, B0L492, B0L493, B0L494, B0L495, B0L496, B0L497, Q8JRC7

genotype 4a, different catalytic efficiencies among NS3/4A proteases from different or similar hepatitis C virus genotypes. Because modulation of enzymatic activity of the protease is dependent on the interactions of a small number of NS4A amino acid residues, the design of small peptidomimetic protease inhibitors may be feasible

695259

drug development

Hepacivirus C

A8DX91, A8DXI7, A8DXT5, B0L492, B0L493, B0L494, B0L495, B0L496, B0L497, Q8JRC7

genotype 4d, different catalytic efficiencies among NS3/4A proteases from different or similar hepatitis C virus genotypes. Because modulation of enzymatic activity of the protease is dependent on the interactions of a small number of NS4A amino acid residues, the design of small peptidomimetic protease inhibitors may be feasible

695259

drug development

Hepacivirus C

-

nonpeptide inhibitors of hepatitis C virus NS3-SP from Chinese medicinal herb Rhodiola kirilowii (Regel) may serve as potential candiate anti-hepatitis C virus agents

684506

drug development

West Nile virus

-

NS2B/NS3 protease crystal structure provides useful guidance in the drug discovery process for related Flavivirus proteases, given the large degree of homology within the family

693529

drug development

Hepacivirus C

-

NS3 protease domain and minimal NS4A cofactor are sufficient to inhibit antiviral signaling through retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5 and block activation of the downstream transcription factors interferon regulatory factor-3 and nuclear factor kappaB, accomplished by protease domain targeting and cleavage of interferon promoter stimulator-1. NS3-4A protease inhibitor therapy of hepatitis C virus infection can effectively remove the NS3-4A blockade to the innate immune response, restoring retinoic acid-inducible gene-I signaling to interferon promoter stimulator-1 and activation of IFN-stimulated gene expression in infected cells

692986

drug development

West Nile virus

-

optimization of tetrapeptide substrates for enhanced protease affinity and processing efficiency provides important clues for developing inhibitors of West Nile Virus infection

692982

drug development

Hepacivirus C

-

series of hepatitis C virus NS3 protease inhibitors comprising a trisubstituted cyclopentane N-acyl-(4R)-hydroxyproline mimic in the P2 position. The frequently used P2 hydroxyproline scaffold can successfully be displaced by a properly substituted cyclopentane scaffold. Further refinements of the compounds may provide even more effective hepatitis C virus NS3 protease inhibitors

691207

drug development

Hepacivirus C

-

very potent NS3 protease inhibitors encompassing the 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid, a N-acyl-Lhydroxyproline mimic, in the P2-position. These inhibitors display two carboxy terminus where the P2 template induces a reversal of direction of the P3/P4 amino acid chain

691209

drug development

Hepatitis C virus genotype 2a

Q99IB8

NS3 protease represents a drug target for treatment of HCV infections

755143

drug development

Hepatitis C virus genotype 1b

P26662

NS3 protease represents a drug target for treatment of HCV infections

752949

drug development

Hepacivirus C

-

NS3 protease represents a drug target for treatment of HCV infections, development of inhibitors less sensitive to drug resistance, overview

752954

drug development

Hepatitis C virus genotype 4a

O39929

NS3/4A is a target for development of direct-acting antiviral agents (DAAs) targeting key viral enzymes essential for viral replication represents a significant milestone in the treatment of chronic HCV infection

753354

drug development

Hepacivirus C

-

the epitopes B1, B8 and B9 are predicted to be ideal candidates for B-cell-based vaccine and are over 95% conserved across six major HCV genotypes. Determination of position and sequences of the peptides that may be used for development of peptide vaccines, overview

752918

medicine

Hepacivirus C

-

natural substrate of enzyme is the mitochondrial antiviral signaling protein. Blocking the cleavage of mitochondrial antiviral signaling protein as means for prevention and treatment of hepatitis C

670679

medicine

Hepacivirus C

-

NS3 protease blunts the ability of hepatitis C virus to induce IFN-alpha promoter activity by proteolytically cleaving MAVS/IPS-1. Hepatitis C virus blocks the synthetic dsRNA-induced signaling pathway at a point upstream of MAVS/IPS-1 by an NS3-independent mechanism

694848

medicine

Hepacivirus C

-

NS3-4A protease has an essential role in the generation of the viral RNA replication machinery. One of the major means by which the virus antagonizes the host cell innate immune response. Viral resistance to most of the NS3-4A inhibitors is going to arise rapidly, at least in the course monotherapy treatment

690304

medicine

Hepacivirus C

-

NS3/4A-mediated trans-activation assay can be used to monitor Hepatitis C virus expression in different cell lines. NS3/4A-dependent chimera can be used to monitor hepatitis C virus infection and to perform the purification of hepatitis C virus-infected cells

693438

medicine

Hepacivirus C

A6N6Q4, A6N6T5

presence of the A156T mutation in close to 1% of NS3 sequences within the liver quasispecies of a chronic Hepatitis C patient never treated with anti-NS3-protease inhibitors

695249

medicine

Hepacivirus C

-

inhibitor shows selective and potent in vitro anti-HCV activity, the potential for combination with other anti-HCV agents, and a favorable pharmacokinetic profile

695639

medicine

hepatitis C virus genotype 1a

-

inhibitor shows selective and potent in vitro anti-HCV activity, the potential for combination with other anti-HCV agents, and a favorable pharmacokinetic profile

695639

medicine

Hepacivirus C

-

inhibitory effects of NS3-4A on antiviral signaling pathways are limited to the Cardif-mediated pathway in human hepatocytes

695940

medicine

Hepacivirus C

-

cleavage of T cell protein tyrosine phosphatase by NS3/4A induces a shift of the intrahepatic immune response toward a nonantiviral Th2-dominated immunity

732266

additional information

Dengue virus

-

domain movements between NS3 protease and NS3 helicase result in the regulation of its activities. NS3 protease increases the stability of subdomain 1 of the RNA helicase. Upon release of the carboxy-terminus from NS3 protease, the residues involved in this interaction are folded back into the last alpha helix. Slow collective motions of NS3. The two lowest-frequency normal modes are enough to describe reorientations of NS3 protease relative to NS3 helicase. Movements induce an increment in the exposure of the active site of NS3 protease that can be important during the proteolytic processing of the viral polyprotein. The third low-frequency normal mode is correlated to subdomain reorientations of NS3 helicase

693699

additional information

Hepacivirus C

-

domain movements between NS3 protease and NS3 helicase result in the regulation of its activities. NS3 protease increases the stability of subdomain 1 of the RNA helicase. Upon release of the carboxy-terminus from NS3 protease, the residues involved in this interaction are folded back into the last alpha helix. Slow collective motions of NS3. The two lowest-frequency normal modes are enough to describe reorientations of NS3 protease relative to NS3 helicase. Movements induce an increment in the exposure of the active site of NS3 protease that can be important during the proteolytic processing of the viral polyprotein. The third low-frequency normal mode is correlated to subdomain reorientations of NS3 helicase

693699

additional information

Kunjin virus

-

participation of the protease domain in promoting the NS3 helicase activity. Protease domain plays an assisting role in the RNA unwinding process

688374