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 ◽  
...  
2009 ◽  
Vol 50 ◽  
pp. S349-S350
Author(s):  
D. Niu ◽  
M. Hagel ◽  
H. Bernard ◽  
L. Qiao ◽  
M. Nacht ◽  
...  

2011 ◽  
Vol 204 (4) ◽  
pp. 609-616 ◽  
Author(s):  
Lee F. Peng ◽  
Esperance A. K. Schaefer ◽  
Nicole Maloof ◽  
Andrew Skaff ◽  
Andrew Berical ◽  
...  

2014 ◽  
Vol 58 (6) ◽  
pp. 3399-3410 ◽  
Author(s):  
Jodi Dufner-Beattie ◽  
Andrew O'Guin ◽  
Stephanie O'Guin ◽  
Aaron Briley ◽  
Bin Wang ◽  
...  

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.


ChemBioChem ◽  
2006 ◽  
Vol 7 (9) ◽  
pp. 1330-1333 ◽  
Author(s):  
Bojana Rakić ◽  
Marc Brûlotte ◽  
Yanouchka Rouleau ◽  
Sylvie Bélanger ◽  
John Paul Pezacki

2011 ◽  
Vol 56 (1) ◽  
pp. 44-53 ◽  
Author(s):  
Hui-Mei Lin ◽  
Jing-Chyi Wang ◽  
Han-Shu Hu ◽  
Pei-Shan Wu ◽  
Chi-Chen Yang ◽  
...  

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.


The Lancet ◽  
2013 ◽  
Vol 381 ◽  
pp. S95
Author(s):  
Ian A Rowe ◽  
Matthew Armstrong ◽  
Richard Parker ◽  
Kathy Guo ◽  
David Adams ◽  
...  

2013 ◽  
Vol 57 (7) ◽  
pp. 3168-3177 ◽  
Author(s):  
Wengang Yang ◽  
Yongnian Sun ◽  
Xiaohong Hou ◽  
Yongsen Zhao ◽  
Joanne Fabrycki ◽  
...  

ABSTRACTTreatment of hepatitis C patients with direct-acting antiviral drugs involves the combination of multiple small-molecule inhibitors of distinctive mechanisms of action. ACH-806 (or GS-9132) is a novel, small-molecule inhibitor specific for hepatitis C virus (HCV). It inhibits viral RNA replication in HCV replicon cells and was active in genotype 1 HCV-infected patients in a proof-of-concept clinical trial (1). Here, we describe a potential mechanism of action (MoA) wherein ACH-806 alters viral replication complex (RC) composition and function. We found that ACH-806 did not affect HCV polyprotein translation and processing, the early events of the formation of HCV RC. Instead, ACH-806 triggered the formation of a homodimeric form of NS4A with a size of 14 kDa (p14) both in replicon cells and in Huh-7 cells where NS4A was expressed alone. p14 production was negatively regulated by NS3, and its appearance in turn was associated with reductions in NS3 and, especially, NS4A content in RCs due to their accelerated degradation. A previously described resistance substitution near the N terminus of NS3, where NS3 interacts with NS4A, attenuated the reduction of NS3 and NS4A conferred by ACH-806 treatment. Taken together, we show that the compositional changes in viral RCs are associated with the antiviral activity of ACH-806. Small molecules, including ACH-806, with this novel MoA hold promise for further development and provide unique tools for clarifying the functions of NS4A in HCV replication.


2011 ◽  
Vol 21 (22) ◽  
pp. 6852-6855 ◽  
Author(s):  
Gopi Kumar Mittapalli ◽  
Andrew Jackson ◽  
Fang Zhao ◽  
Haekyung Lee ◽  
Stephine Chow ◽  
...  

PLoS ONE ◽  
2012 ◽  
Vol 7 (4) ◽  
pp. e35351 ◽  
Author(s):  
Glen A. Coburn ◽  
Danielle N. Fisch ◽  
Sameer M. Moorji ◽  
Jean-Marc de Muys ◽  
Jose D. Murga ◽  
...  

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