Literature summary for 3.4.21.98 extracted from

De Francesco, R.; Carfi, A.
Advances in the development of new therapeutic agents targeting the NS3-4A serine protease or the NS5B RNA-dependent RNA polymerase of the hepatitis C virus (2007), Adv. Drug Deliv. Rev., 59, 1242-1262.

Search for more literature for 3.4.21.98

Application

Application	Comment	Organism
medicine	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	Hepacivirus C

Crystallization (Commentary)

Crystallization (Comment)	Organism
NS3-4A is made of two domains both composed of a beta-barrel and two short alpha-helices with the catalytic triad located in a crevice formed at the interface between the two domains. NS3-4A protease in complex with inhibitors	Hepacivirus C

Protein Variants

Protein Variants	Comment	Organism
A156S	confers resistance to SCH-503034	Hepacivirus C
A156S	reduced sensitivity to BILN-2061, fully catalytically functional	Hepacivirus C
A156T	reduced sensitivity to BILN-2061, confers high levels of resistance to SCH-503034 fully catalytically functional	Hepacivirus C
A156V	reduced sensitivity to BILN-2061, confers high levels of resistance to SCH-503034, fully catalytically functional	Hepacivirus C
D158A	reduced sensitivity to BILN-2061, fully catalytically functional	Hepacivirus C
D158V	reduced sensitivity to BILN-2061, fully catalytically functional	Hepacivirus C
D168A	reduced sensitivity to BILN-2061, fully catalytically functional	Hepacivirus C
D168V	reduced sensitivity to BILN-2061, fully catalytically functional	Hepacivirus C
R155K	confers moderate level of resistance to SCH-503034	Hepacivirus C
R155M	confers moderate level of resistance to SCH-503034	Hepacivirus C
R155Q	reduced sensitivity to BILN-2061, fully catalytically functional	Hepacivirus C
R155S	confers moderate level of resistance to SCH-503034	Hepacivirus C
R155T	confers moderate level of resistance to SCH-503034	Hepacivirus C
T54A	confers moderate level of resistance to SCH-503034 and low-level of resistance to BILN-2061	Hepacivirus C
T54S	confers moderate level of resistance to SCH-503034	Hepacivirus C
V170A	does not affect replicon fitness, confers resistance to SCH-503034 and low-level of resistance to BILN-2061	Hepacivirus C
V36A	confers moderate level of resistance to SCH-503034	Hepacivirus C
V36L	confers moderate level of resistance to SCH-503034	Hepacivirus C
V36M	confers moderate level of resistance to SCH-503034	Hepacivirus C

Inhibitors

Inhibitors	Comment	Organism	Structure
BILN-2061	used in clinical trials. Potently inhibits Hepatitis C virus replication in human hepatoma cells, but causes cardiac toxicity in experimental animals	Hepacivirus C
GS-9132	an acylthiourea with in vitro activity against Hepatitis C virus genotype 1, inhibits the formation of a functional replication complex. Reversible nephrotoxicity in clinical trials	Hepacivirus C
ITMN-191	high in vitro potency and specificity	Hepacivirus C
additional information	protease is susceptible to feedback inhibition by the N-terminal products released from the polyprotein substrate after enzymatic cleavage	Hepacivirus C
SCH-503034	used in clinical trials. Orally bioavailable, covalent, reversible alpha-keto amide inhibitor. Displays potent and time-dependent inhibition of the NS3-4A protease. Inhibitor dissociation constant in the low nanomolar range. Ability to effectively inhibit Hepatitis C virus RNA synthesis in the human hepatoma cells harboring the hepatitis C virus replicon	Hepacivirus C
VX-950	used in clinical trials. Orally biovailable tetrapeptide alpha-ketoamide, binds slowly and reversibly to the protease, with an affinity for the genotype 1 Hepatitis C virus NS4-4A protease in the low nanomolar range and a half life of nearly an hour. Moderately potent inhibitor of Hepatitis C virus replication. Achieves a more than a 10000fold suppression of hepatitis C virus RNA in replicon cells treated for 14 days in the presence of relatively low concentrations of the compound	Hepacivirus C

Organism

Organism	UniProt	Comment	Textmining
Hepacivirus C	-	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
CARDIF + H2O	-	Hepacivirus C	?	-	?
additional information	enzyme's requirement of peptide substrates of 10 amino acids in length, spanning from P6 to P4'	Hepacivirus C	?	-	?
TRIF + H2O	-	Hepacivirus C	?	-	?
viral polyprotein + H2O	proteolytic cleavage at the four junctions NS3/NS4A, NS5A/NS5B, NS4A/NS4B and NS4B/NS5A. NS3-dependent cleavage sites of the polyprotein have the consensus sequence Asp/Glu-(Xaa)4-Cys/Thr-Ser/Ala-(Xaa)2-Leu/Trp/Tyr, with the most efficient cleavage occurring after cysteine	Hepacivirus C	?	-	?

Synonyms

Synonyms	Comment	Organism
NS3-4A serine protease	-	Hepacivirus C

Cofactor

Cofactor	Comment	Organism	Structure
additional information	requires the noncovalently-associated viral protein NS4A for optimal catalytic activity. NS4A increases the enzymatic activity of NS3 by stabilizing the N-terminal domain of the protease, by optimizing the orientation of the residues of the catalytic triad and by contributing to the formation of the substrate recognition site	Hepacivirus C

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism	Structure
0.000044	-	VX-950	-	Hepacivirus C

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor	Structure
0.0000025	-	-	Hepacivirus C	ITMN-191
0.000003	-	-	Hepacivirus C	BILN-2061

Use of this online version of BRENDA is free under the CC BY 4.0 license. See terms of use for full details.

Release 2023.1 (January 2023)