Structure-Based Macrocyclization Yields Hepatitis C Virus NS5B Inhibitors with Improved Binding Affinities and Pharmacokinetic Properties

2012 ◽  
Vol 51 (19) ◽  
pp. 4637-4640 ◽  
Author(s):  
Maxwell D. Cummings ◽  
Tse-I Lin ◽  
Lili Hu ◽  
Abdellah Tahri ◽  
David McGowan ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Binding Affinities ◽  
Pharmacokinetic Properties

Structure-Based Macrocyclization Yields Hepatitis C Virus NS5B Inhibitors with Improved Binding Affinities and Pharmacokinetic Properties

2012 ◽  
Vol 124 (19) ◽  
pp. 4715-4718 ◽  
Author(s):  
Maxwell D. Cummings ◽  
Tse-I Lin ◽  
Lili Hu ◽  
Abdellah Tahri ◽  
David McGowan ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Binding Affinities ◽  
Pharmacokinetic Properties

scholarly journals Preclinical Profile and Clinical Efficacy of a Novel Hepatitis C Virus NS5A Inhibitor, EDP-239

2016 ◽  
Vol 60 (10) ◽  
pp. 6207-6215 ◽  
Author(s):  
Christopher M. Owens ◽  
Bradley B. Brasher ◽  
Alex Polemeropoulos ◽  
Michael H. J. Rhodin ◽  
Nicole McAllister ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nonstructural Protein ◽  
Viral Rna ◽  
Controlled Clinical Trial ◽  
Genotype 1A ◽  
Pharmacokinetic Properties ◽  
Direct Acting

ABSTRACTEDP-239, a novel hepatitis C virus (HCV) inhibitor targeting nonstructural protein 5A (NS5A), has been investigatedin vitroandin vivo. EDP-239 is a potent, selective inhibitor with potency at picomolar to nanomolar concentrations against HCV genotypes 1 through 6. In the presence of human serum, the potency of EDP-239 was reduced by less than 4-fold. EDP-239 is additive to synergistic with other direct-acting antivirals (DAAs) or host-targeted antivirals (HTAs) in blocking HCV replication and suppresses the selection of resistancein vitro. Furthermore, EDP-239 retains potency against known DAA- or HTA-resistant variants, with half-maximal effective concentrations (EC50s) equivalent to those for the wild type. In a phase I, single-ascending-dose, placebo-controlled clinical trial, EDP-239 demonstrated excellent pharmacokinetic properties that supported once daily dosing. A single 100-mg dose of EDP-239 resulted in reductions in HCV genotype 1a viral RNA of >3 log10IU/ml within the first 48 h after dosing and reductions in genotype 1b viral RNA of >4-log10IU/ml within 96 h. (This study has been registered at ClinicalTrials.gov under identifier NCT01856426.)

scholarly journals Best treatment for chronic hepatitis C virus infection

2002 ◽  
Vol 6 (42) ◽  
Author(s):  
H Harris
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Chemical Properties ◽  
Clinical Excellence ◽  
Pegylated Interferon ◽  
Dosing Regimen ◽  
European Guidelines ◽  
The United Kingdom ◽  
Pharmacokinetic Properties ◽  
And Chemical Properties

The current European guidelines recommend that interferon alfa be given in combination with ribavirin as the treatment of choice for patients with moderate or severe hepatitis C virus (HCV) related disease (1). In the United Kingdom, the National Institute for Clinical Excellence (NICE) has endorsed this therapy (2). Recently, however, two types of pegylated interferon, which differ in their pharmacokinetic and chemical properties, have been produced. The addition of polyethyleneglycol to the standard interferon molecule extends its half life thus allowing a more convenient once-weekly dosing regimen with more favourable pharmacokinetic properties.

scholarly journals A 7-Deaza-Adenosine Analog Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic Properties

2004 ◽  
Vol 48 (10) ◽  
pp. 3944-3953 ◽  
Author(s):  
David B. Olsen ◽  
Anne B. Eldrup ◽  
Linda Bartholomew ◽  
Balkrishen Bhat ◽  
Michele R. Bosserman ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Treatment Options ◽  
Lethal Dose ◽  
Current Treatment ◽  
Hcv Infection ◽  
Hcv Rna ◽  
Inhibitory Potency ◽  
Pharmacokinetic Properties

ABSTRACT Improved treatments for chronic hepatitis C virus (HCV) infection are needed due to the suboptimal response rates and deleterious side effects associated with current treatment options. The triphosphates of 2′-C-methyl-adenosine and 2′-C-methyl-guanosine were previously shown to be potent inhibitors of the HCV RNA-dependent RNA polymerase (RdRp) that is responsible for the replication of viral RNA in cells. Here we demonstrate that the inclusion of a 7-deaza modification in a series of purine nucleoside triphosphates results in an increase in inhibitory potency against the HCV RdRp and improved pharmacokinetic properties. Notably, incorporation of the 7-deaza modification into 2′-C-methyl-adenosine results in an inhibitor with a 20-fold-increased potency as the 5′-triphosphate in HCV RdRp assays while maintaining the inhibitory potency of the nucleoside in the bicistronic HCV replicon and with reduced cellular toxicity. In contrast, while 7-deaza-2′-C-methyl-GTP also displays enhanced inhibitory potency in enzyme assays, due to poor cellular penetration and/or metabolism, the nucleoside does not inhibit replication of a bicistronic HCV replicon in cell culture. 7-Deaza-2′-C-methyl-adenosine displays promising in vivo pharmacokinetics in three animal species, as well as an acute oral lethal dose in excess of 2,000 mg/kg of body weight in mice. Taken together, these data demonstrate that 7-deaza-2′-C-methyl-adenosine is an attractive candidate for further investigation as a potential treatment for HCV infection.

scholarly journals Human hepatic glyceraldehyde-3-phosphate dehydrogenase binds to the poly(U) tract of the 3′ non-coding region of hepatitis C virus genomic RNA

1999 ◽  
Vol 80 (12) ◽  
pp. 3109-3113 ◽  
Author(s):  
Juraj Petrik ◽  
Hayley Parker ◽  
Graeme J. M. Alexander
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Middle Part ◽  
Hcv Rna ◽  
Binding Affinities ◽  
Genomic Rna ◽  
Coding Region ◽  
Multifunctional Protein ◽  
Polypyrimidine Tract Binding Protein ◽  
Replicase Complex

The unique poly(U/UC) tract, the middle part of the tripartite 3′ non-coding region (3′NCR) of hepatitis C virus (HCV) genomic RNA, may represent a recognition signal for the HCV replicase complex. In this study, several proteins binding specifically to immobilized ribooligonucleotide r(U)25 mimicking this structure were identified using cytosolic extracts from HCV-negative or -positive liver explants, and a prominent 36 kDa protein was studied further. Competition experiments including homoribopolymers revealed binding affinities in the order: oligo/poly(U)≫(A)≫(C)≫(G). The protein was identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a multifunctional protein known to bind RNA. GAPDH bound efficiently to the full-length HCV RNA and binding to various 3′NCR constructs revealed critical dependence upon the presence of the middle part of the 3′NCR. Polypyrimidine tract-binding protein, described previously to bind the 3′NCR, did not bind efficiently to the middle part of 3′NCR and was captured from liver extracts in considerably smaller quantities.

HEPATITIS C VIRUS INFECTION (AND ADDITIONAL NEOPLASMS) AMONG MARGINAL ZONE LYMPHOMAS

1997 ◽  
Vol 96 (2) ◽  
pp. 427-428 ◽  
Author(s):  
FREDERICO SILVESTRI ◽  
GIOVANNI BARILLARI ◽  
RENATO FANIN ◽  
FLAVIA SALMASO ◽  
LAURA INFANTI ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Infection ◽  
Marginal Zone ◽  
Hepatitis C Virus Infection
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