Hepatitis C virus (HCV) is a positive-strand RNA virus grouped in the genus Hepacivirus within the family Flaviviridae. HCV is classified into at least 6 genotypes (gt), and its error-prone polymerase leads to more than 50 subtypes. The long open reading frame, which encodes the HCV polyprotein, is processed by host and viral proteases and gives rise to three structural proteins (the capsid protein core and envelope glycoproteins E1 and E2) and seven nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). NS2 and p7 are essential for virus assembly but not RNA replication, whereas NS3 to NS5B are involved in a membrane-associated RNA replicase complex (RC). The NS3 protein is composed of a serine protease and an RNA helicase/nucleoside triphosphatase (NTPase), NS4A serves as a cofactor for NS3 serine protease, NS5B is the RNA-dependent RNA polymerase, and NS5A is considered to play key roles in multiple steps of the HCV life cycle.NS5A inhibitors exhibit a rapid inhibition of virus infectivity shortly after administration to HCV-infected cells.
The HCV protein NS5A prevents the apoptosis-enabling loss of intracellular potassium by inhibiting Kv2.1 function and thus blocking hepatocyte cell death.
The HCV RNA-dependent RNA polymerase (RdRp) has long been a prime target for antiviral development because of its critical role in viral replication and the absence of a mammalian homologous enzyme.
The combination of lucidone and alpha interferon, the protease inhibitor Telaprevir, the NS5A inhibitor BMS-790052, or the NS5B polymerase inhibitor PSI-7977, synergistically suppresses HCV RNA replication.
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Ravidasvir (PPI-668;BI 238630) is a potent pan-genotypic HCV NS5A inhibitor with IC50 of 0.12/0.01/1.14 nM for HCV gt-1a/1b/3a in replicon luciferase assay; has been well tolerated and shown high sustained viral response rates as a key component in all-oral combination regimens in multiple human clinical trials.
Velpatasvir (GS-5816) is a second generation, pan-genotypic inhibitor of HCV NS5A, demonstrates a high barrier to resistance in HCV replicon assays.
GSK-2485852 (GSK2485852, GSK5852) is a highly potent, selective HCV NS5B polymerase inhibitor with IC50 of 3.0 and 1.6 nM for HCV genotypes 1a and 1b in replicon assay, respectively; displays an excellent resistance profile and shows a <5-fold potency loss across the clinically important NS5B resistance mutations P495L, M423T, C316Y, and Y448H; targets NNI palm site 2 of NS5B and inhibits all HCV genotypes.
BMS-929075 is a highly potent, selective, orally bioavailable HCV NS5B polymerase inhibitor with IC50 of 9, 4, and 18 nM for GT1a, GT1b, and GT1b-C316N mutant in HCV replicon assay, respectively; possesses excellent pharmacokinetic parameters across preclinical animal species.
GSK-625433 is a highly potent, selective HCV NS5B polymerase inhibitor for treatment of HCV infection.
Ruzasvir is a potent, pan-genotype HCV NS5A inhibitor with replicon EC90 of 0.003, 0.016, 0.067, 0.036, 0.007, and 0.007 nM for GT1a, GT1a L31V, GT1a Y93H, GT2b, GT3a, and Gt4a, respectively.
INX-08189 is a phosphoramidate prodrug of O-6-methyl-2-C-methyl guanosine, potent inhibitor of HCV NS5B polymerase with IC50 of 10 nM in replicon assay; inhibits viral replication with EC50 of 35 nM, inhibits mutant NS5b S282T mutant replicon with EC90 of 344 nM; orally active.
Coblopasvir (KW136, KW-136) is a novel HCV NS5A inhibitor under development for treatment of HCV infection.
Cyclophilin inhibitor C31
Cyclophilin inhibitor C31 (SMCypI C31) is a small-molecule cyclophilin (CypA) inhibitor (SMCypI) with PPIase inhibition IC50 of 0.1 uM, displays anti-HCV activity (HCV Gt1b replicon EC50=0.4 uM) and disrupts the CypA-NS5A interaction; exerts at least additive antiviral effects when combined with the NS5A inhibitor ledipasvir and is fully active against ledipasvir-resistant viruses; also inhibits the replication of other members of the Flaviviridae family (DENV EC50=7.3 uM), YFV EC50, 27.2 uM, and ZIKV EC50=48.0 uM), without significant cytotoxicity.
Pibrentasvir (ABT-530) is a novel and pan-genotypic HCV NS5A inhibitor with EC50 of 1.4-5.0 pM against HCV replicons containing NS5A genotypes 1-6; demonstrates potent antiviral activity and acceptable safety during 3-day monotherapy in patients with HCV genotype 1 infection, with or without compensated cirrhosis.
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