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Literature summary for 3.4.21.98 extracted from

  • Oezen, A.; Prachanronarong, K.; Matthew, A.N.; Soumana, D.I.; Schiffer, C.A.
    Resistance outside the substrate envelope hepatitis C NS3/4A protease inhibitors (2019), Crit. Rev. Biochem. Mol. Biol., 54, 11-26 .
    View publication on PubMed

Protein Variants

Protein Variants Comment Organism
additional information drug resistance mutations at residues R155, A156, and D168, are located close to the catalytic triad, impact the most inhibitors Hepatitis C virus genotype 1b
Q80K Q80K is a polymorphism that impacts the activity of most protease inhibitors. Enzyme inhibitors boceprevir, telaprevir, simeprevir, danoprevir, asunaprevir, and faldaprevir are susceptible to mutations at Q80 Hepatitis C virus genotype 1b
R155K/V36M a drug-resistant mutant Hepatitis C virus genotype 1b

Inhibitors

Inhibitors Comment Organism Structure
asunaprevir
-
Hepatitis C virus genotype 1b
boceprevir
-
Hepatitis C virus genotype 1b
danoprevir
-
Hepatitis C virus genotype 1b
faldaprevir
-
Hepatitis C virus genotype 1b
glecaprevir
-
Hepatitis C virus genotype 1b
grazoprevir
-
Hepatitis C virus genotype 1b
MK-5172
-
Hepatitis C virus genotype 1b
additional information structural analysis, differences in how inhibitors fit within the substrate envelope and interact with the binding site trend with differential drug resistance patterns, hydrogen bond interactions between ligands and side chain atoms in the HCV NS3/4A protease active site, and differential van der Waals interactions on the binding surface of HCV NS3/4A protease, detailed overview. There are many basic residues in the S6 pocket, such as R119, R123, R161, and K165, which make conserved interactions with the conserved acidic D or E residue at the P6 position of the substrate. A drug design strategies focusing on inhibitors with a P1-P3 macrocycle and flexible quinoxiline-related P2 moieties may be an optimal strategy, given high potency can be achieved without compromising the resistance profile. Another drug design strategy is extending inhibitors in the P1' and P4-P6 regions to make increased contacts with conserved residues in the S1' and S4-S6 pockets to increase inhibitor potency while decreasing susceptibility to drug resistance mutations. Q80K is a polymorphism that impacts the activity of most protease inhibitors. Boceprevir, telaprevir, simeprevir, danoprevir, asunaprevir, and faldaprevir are susceptible to mutations at Q80. Drug resistance mutations at residues R155, A156, and D168, are located close to the catalytic triad, impact the most inhibitors. Boceprevir and telaprevir are the oldest inhibitors and are susceptible to drug resistance, with main drug resistance mutations at residues V36, T54, R155, and A156 Hepatitis C virus genotype 1b
narlaprevir
-
Hepatitis C virus genotype 1b
paritaprevir
-
Hepatitis C virus genotype 1b
simeprevir
-
Hepatitis C virus genotype 1b
sovaprevir
-
Hepatitis C virus genotype 1b
telaprevir
-
Hepatitis C virus genotype 1b
vaniprevir
-
Hepatitis C virus genotype 1b
vedroprevir
-
Hepatitis C virus genotype 1b

Localization

Localization Comment Organism GeneOntology No. Textmining

Organism

Organism UniProt Comment Textmining
Hepatitis C virus genotype 1b P26662 HCV, isolate Japanese
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
additional information viral substrates of HCV NS3/4A protease share a conserved binding shape at the active site. Comparison of amino acid cleavage site sequences of four HCV NS3/4A protease viral substrates. Substrates fill a conserved volume within the active site known as the substrate envelope, and primary drug resistance mutations occur where inhibitors protrude outside of the substrate envelope. These residues are often not evolutionarily conserved or are not necessary for biological function Hepatitis C virus genotype 1b ?
-
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Synonyms

Synonyms Comment Organism
HCV NS3/4A protease
-
Hepatitis C virus genotype 1b
nonstructural protein 3/4A protease
-
Hepatitis C virus genotype 1b
NS3/4A protease
-
Hepatitis C virus genotype 1b

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.00000014
-
grazoprevir pH and temperature not specified in the publication Hepatitis C virus genotype 1b
0.00000036
-
simeprevir pH and temperature not specified in the publication Hepatitis C virus genotype 1b
0.0000004
-
asunaprevir pH and temperature not specified in the publication Hepatitis C virus genotype 1b
0.00000074
-
vaniprevir pH and temperature not specified in the publication Hepatitis C virus genotype 1b
0.00000097
-
faldaprevir pH and temperature not specified in the publication Hepatitis C virus genotype 1b
0.000001
-
danoprevir pH and temperature not specified in the publication Hepatitis C virus genotype 1b
0.000007
-
narlaprevir pH and temperature not specified in the publication Hepatitis C virus genotype 1b
0.000014
-
boceprevir pH and temperature not specified in the publication Hepatitis C virus genotype 1b
0.0000344
-
telaprevir pH and temperature not specified in the publication Hepatitis C virus genotype 1b