scholarly journals Resistance Analysis and Characterization of a Thiazole Analogue, BP008, as a Potent Hepatitis C Virus NS5A Inhibitor

2011 ◽  
Vol 56 (1) ◽  
pp. 44-53 ◽  
Author(s):  
Hui-Mei Lin ◽  
Jing-Chyi Wang ◽  
Han-Shu Hu ◽  
Pei-Shan Wu ◽  
Chi-Chen Yang ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Small Molecule ◽  
Synergistic Effects ◽  
Treatment Strategies ◽  
Small Molecule Inhibitor ◽  
Hcv Infection ◽  
Molecule Inhibitor ◽  
Ns5b Polymerase Inhibitor ◽  
Chronic Hcv

ABSTRACTHepatitis C virus (HCV) is a global health problem, affecting approximately 3% of the world's population. The standard treatment for HCV infection is often poorly tolerated and ineffective. Therefore, the development of novel or more effective treatment strategies to treat chronic HCV infection is urgently needed. In this report, BP008, a potent small-molecule inhibitor of HCV replication, was developed from a class of compounds with thiazol core structures by means of utilizing a cell-based HCV replicon system. The compound reduced the reporter expression of the HCV1b replicon with a 50% effective concentration (EC50) and selective index value of 4.1 ± 0.7 nM and >12,195, respectively. Sequencing analyses of several individual clones derived from BP008-resistant RNAs purified from cells harboring HCV1b replicon revealed that amino acid substitutions mainly within the N-terminal region (domain I) of NS5A were associated with decreased inhibitor susceptibility. Q24L, P58S, and Y93H are the key substitutions for resistance selection; F149L and V153M play the compensatory role in the replication and drug resistance processes. Moreover, BP008 displayed synergistic effects with alpha interferon (IFN-α), NS3 protease inhibitor, and NS5B polymerase inhibitor, as well as good oral bioavailability in SD rats and favorable exposure in rat liver. In summary, our results pointed to an effective small-molecule inhibitor, BP008, that potentially targets HCV NS5A. BP008 can be considered a part of a more effective therapeutic strategy for HCV in the future.

scholarly journals A Novel Small Molecule Inhibitor of Hepatitis C Virus Entry

2010 ◽  
Vol 6 (9) ◽  
pp. e1001086 ◽  
Author(s):  
Carl J. Baldick ◽  
Michael J. Wichroski ◽  
Annapurna Pendri ◽  
Ann W. Walsh ◽  
Jie Fang ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Small Molecule ◽  
Virus Entry ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

962 PROTEIN SILENCING OF HEPATITIS C VIRUS PROTEASE WITH A SMALL MOLECULE INHIBITOR: DISCOVERY OF AVL-181

2009 ◽  
Vol 50 ◽  
pp. S349-S350
Author(s):  
D. Niu ◽  
M. Hagel ◽  
H. Bernard ◽  
L. Qiao ◽  
M. Nacht ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Inhibitor Discovery

scholarly journals Ceestatin, a Novel Small Molecule Inhibitor of Hepatitis C Virus Replication, Inhibits 3-Hydroxy-3-Methylglutaryl-Coenzyme A Synthase

2011 ◽  
Vol 204 (4) ◽  
pp. 609-616 ◽  
Author(s):  
Lee F. Peng ◽  
Esperance A. K. Schaefer ◽  
Nicole Maloof ◽  
Andrew Skaff ◽  
Andrew Berical ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Replication ◽  
Small Molecule ◽  
Coenzyme A ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

scholarly journals Identification of AP80978, a Novel Small-Molecule Inhibitor of Hepatitis C Virus Replication That Targets NS4B

2014 ◽  
Vol 58 (6) ◽  
pp. 3399-3410 ◽  
Author(s):  
Jodi Dufner-Beattie ◽  
Andrew O'Guin ◽  
Stephanie O'Guin ◽  
Aaron Briley ◽  
Bin Wang ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Small Molecule ◽  
Antiviral Drug ◽  
Small Molecule Inhibitor ◽  
Site Directed Mutagenesis ◽  
Subgenomic Replicon ◽  
Content Type ◽  
Genotype 1B ◽  
Molecule Inhibitor

ABSTRACTA small-molecule inhibitor of hepatitis C virus (HCV) designated AP89652 was identified by screening a compound library with an HCV genotype 1b subgenomic replicon assay. AP89652 contains two chiral centers, and testing of twosynenantiomers revealed that activity in the replicon assay resided with only one, AP80978, whose 50% effective concentration (EC50) (the concentration at which a 50% reduction inRenillaluciferase levels was observed relative to an untreated control) was 630 nM. AP80978 was inhibitory against HCV genotypes 1a and 1b but not genotype 2a. In a replicon clearance assay, the potency and clearance rate of AP80978 were similar to those of telaprevir (VX950) and cyclosporine (CsA). AP80978 was nontoxic when tested against a panel of human cell lines, and inhibitory activity was HCV specific in that there was limited activity against negative-strand viruses, an alphavirus, and flaviviruses. By selection of resistant replicons and assessment of activity in genotype 1b/2a intergenotypic replicons, the viral protein target of this compound was identified as NS4B. NS4B F98V/L substitutions were confirmed by site-directed mutagenesis as AP80978 resistance-associated mutations. When tested against HCV produced in cell culture, the compound was significantly more potent than other HCV inhibitors, including VX950, CsA, and 2′-C-methyladenosine (2′C-meA). In addition, AP80977, the enantiomer that was inactive in the replicon assay, had activity against the virus, although it was lower than the activity of AP80978. These results suggest that AP80978 has the potential to be optimized into an effective antiviral drug and is a useful tool to further study the role of NS4B in HCV replication.

Bleomycin is a Potent Small-Molecule Inhibitor of Hepatitis C Virus Replication

ChemBioChem ◽  
2006 ◽  
Vol 7 (9) ◽  
pp. 1330-1333 ◽  
Author(s):  
Bojana Rakić ◽  
Marc Brûlotte ◽  
Yanouchka Rouleau ◽  
Sylvie Bélanger ◽  
John Paul Pezacki
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Replication ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

scholarly journals Mechanisms Underlying Hepatitis C Virus-Associated Hepatic Fibrosis

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1249 ◽  
Author(s):  
Mousumi Khatun ◽  
Ratna B. Ray
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Treatment Strategies ◽  
Hcv Infection ◽  
Direct Acting Antiviral ◽  
Cytokines And Chemokines ◽  
Chronic Hcv

Hepatitis C virus (HCV) infection often causes liver diseases, including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Liver fibrosis is the outcome of the wound healing response to tissue damage caused by chronic HCV infection. This process is characterized by the excessive accumulation of extracellular matrix (ECM) proteins, such as collagen fibers secreted by activated hepatic stellate cells (HSCs). Activation of HSCs from the quiescent stage is mediated by different mechanisms, including pro-inflammatory cytokines and chemokines released from HCV-infected hepatocytes and liver macrophages. HCV infection modulates the expression of different microRNAs that can be transported and delivered to the HSCs via exosomes released from infected cells, also leading to the development of advanced disease pathogenesis. Although recent advancements in direct-acting antiviral (DAA) treatment can efficiently control viremia, there are very few treatment strategies available that can be effective at preventing pathogenesis in advanced liver fibrosis or cirrhosis in patients. Assessment of fibrosis is considered to be the major part of proper patient care and decision making in clinical practice. In this review, we highlighted the current knowledge of molecular mechanisms responsible for the progression of liver fibrosis in chronically HCV-infected patients, and currently available methods for evaluation of fibrosis in patients. A detailed understanding of these aspects at the molecular level may contribute to the development of new therapies targeting HCV-related liver fibrosis.

Hepatitis C virus kinetics after liver transplantation to study the role of a small molecule inhibitor of viral entry

The Lancet ◽  
2013 ◽  
Vol 381 ◽  
pp. S95
Author(s):  
Ian A Rowe ◽  
Matthew Armstrong ◽  
Richard Parker ◽  
Kathy Guo ◽  
David Adams ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Small Molecule ◽  
Viral Entry ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

Genetic polymorphisms as the predictors of response to antiviral treatment in chronic hepatitis C virus infection

2011 ◽  
Vol 152 (22) ◽  
pp. 876-881
Author(s):  
Alajos Pár
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Genetic Polymorphisms ◽  
Chronic Hepatitis C ◽  
Genome Wide Association Study ◽  
Antiviral Treatment ◽  
Hcv Infection ◽  
Snp Analysis ◽  
Chronic Hcv

The review discusses the genetic polymorphisms involved in the pathogenesis of hepatitis C virus (HCV) infection, that may determine the outcome of disease. In this field earlier both certain major histocompatibility complex (MHC) alleles and some cytokine gene variants have also been studied. Recently, the genome-wide association study (GWAS) and targeted single nucleotide polymorphism (SNP) analysis have revealed that a variant in the promoter region of interleukin-28B (IL-28B) gene is strongly linked to viral clearance and it may be the strongest pretreatment predictor of treatment response in chronic hepatitis C. Last year it was shown that two genetic variants leading to inosine triphosphatase deficiency protect against haemolytic anemia in patients receiving ribavirin during antiviral treatment for chronic HCV infection. Orv. Hetil., 2011, 152, 876–881.

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