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 | 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 | Comment | Organism | GeneOntology No. | Textmining |
---|
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Hepatitis C virus genotype 1b | P26662 | HCV, isolate Japanese | - |
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 | ? | - |
? |
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 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 |