Allosteric N-acetamide-indole-6-carboxylic acid thumb pocket 1 inhibitors of hepatitis C virus NS5B polymerase — Acylsulfonamides and acylsulfamides as carboxylic acid replacements

2013 ◽  
Vol 91 (1) ◽  
pp. 66-81 ◽  
Author(s):  
Pierre L. Beaulieu ◽  
René Coulombe ◽  
James Gillard ◽  
Christian Brochu ◽  
Jianmin Duan ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Carboxylic Acid ◽  
Allosteric Inhibitors ◽  
Subgenomic Replicon ◽  
Structure Activity ◽  
Hcv Ns5b ◽  
Acid Function ◽  
Ns5b Polymerase

Acylsulfonamide and acylsulfamide as surrogates for the carboxylic acid function of N-acetamide-indole-6-carboxylic acids were evaluated as allosteric inhibitors of hepatitis C virus (HCV) NS5B polymerase. Several analogs displayed excellent antiviral potency against both 1a and 1b HCV genotypes in cell-based subgenomic replicon assays. Structure–activity relationships (SAR) are discussed in the context of the crystal structure of an inhibitor − NS5B polymerase complex. Absorption, distribution, metabolism, and excretion pharmacokinetic (ADME-PK) properties of this class of inhibitors are also described.

Structure–Activity Relationship (SAR) Development and Discovery of Potent Indole-Based Inhibitors of the Hepatitis C Virus (HCV) NS5B Polymerase

2012 ◽  
Vol 55 (2) ◽  
pp. 754-765 ◽  
Author(s):  
Kevin X. Chen ◽  
Bancha Vibulbhan ◽  
Weiying Yang ◽  
Mousumi Sannigrahi ◽  
Francisco Velazquez ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Structure Activity ◽  
Hcv Ns5b ◽  
Ns5b Polymerase

The discovery and structure–activity relationships of pyrano[3,4-b]indole based inhibitors of hepatitis C virus NS5B polymerase

2010 ◽  
Vol 20 (9) ◽  
pp. 2968-2973 ◽  
Author(s):  
Matthew G. LaPorte ◽  
Tandy L. Draper ◽  
Lori E. Miller ◽  
Charles W. Blackledge ◽  
Lara K. Leister ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Ns5b Polymerase

Potent Inhibitors of Subgenomic Hepatitis C Virus RNA Replication through Optimization of Indole-N-Acetamide Allosteric Inhibitors of the Viral NS5B Polymerase

2005 ◽  
Vol 48 (14) ◽  
pp. 4547-4557 ◽  
Author(s):  
Steven Harper ◽  
Salvatore Avolio ◽  
Barbara Pacini ◽  
Marcello Di Filippo ◽  
Sergio Altamura ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Replication ◽  
Hepatitis C Virus Rna ◽  
Allosteric Inhibitors ◽  
Virus Rna ◽  
Ns5b Polymerase

Phosphoramidate Dinucleosides as Inhibitors of Hepatitis C Virus Subgenomic Replicon and NS5B Polymerase Activity

2011 ◽  
Vol 90 (2) ◽  
pp. A75
Author(s):  
S. Priet ◽  
I. Zlatev ◽  
I. Barvik ◽  
J. Neyts ◽  
H. Dutartre ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Polymerase Activity ◽  
Subgenomic Replicon ◽  
Ns5b Polymerase

scholarly journals In VitroActivity and Resistance Profile of Dasabuvir, a Nonnucleoside Hepatitis C Virus Polymerase Inhibitor

2014 ◽  
Vol 59 (3) ◽  
pp. 1505-1511 ◽  
Author(s):  
Warren Kati ◽  
Gennadiy Koev ◽  
Michelle Irvin ◽  
Jill Beyer ◽  
Yaya Liu ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Clinical Isolates ◽  
Genotype 1 ◽  
Subgenomic Replicon ◽  
Hcv Genotype ◽  
Genotype 1A ◽  
Treatment Naïve ◽  
Hcv Genotype 1 ◽  
Hcv Ns5b

ABSTRACTDasabuvir (ABT-333) is a nonnucleoside inhibitor of the RNA-dependent RNA polymerase encoded by the hepatitis C virus (HCV) NS5B gene. Dasabuvir inhibited recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates, with 50% inhibitory concentration (IC50) values between 2.2 and 10.7 nM, and was at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases. In the HCV subgenomic replicon system, dasabuvir inhibited genotype 1a (strain H77) and 1b (strain Con1) replicons with 50% effective concentration (EC50) values of 7.7 and 1.8 nM, respectively, with a 13-fold decrease in inhibitory activity in the presence of 40% human plasma. This level of activity was retained against a panel of chimeric subgenomic replicons that contained HCV NS5B genes from 22 genotype 1 clinical isolates from treatment-naive patients, with EC50s ranging between 0.15 and 8.57 nM. Maintenance of replicon-containing cells in medium containing dasabuvir at concentrations 10-fold or 100-fold greater than the EC50resulted in selection of resistant replicon clones. Sequencing of the NS5B coding regions from these clones revealed the presence of variants, including C316Y, M414T, Y448C, Y448H, and S556G, that are consistent with binding to the palm I site of HCV polymerase. Consequently, dasabuvir retained full activity against replicons known to confer resistance to other polymerase inhibitors, including the S282T variant in the nucleoside binding site and the M423T, P495A, P495S, and V499A single variants in the thumb domain. The use of dasabuvir in combination with inhibitors targeting HCV NS3/NS4A protease (ABT-450 with ritonavir) and NS5A (ombitasvir) is in development for the treatment of HCV genotype 1 infections.

scholarly journals Mutations in NS5B Polymerase of Hepatitis C Virus: Impacts on in Vitro Enzymatic Activity and Viral RNA Replication in the Subgenomic Replicon Cell Culture

Virology ◽  
2002 ◽  
Vol 297 (2) ◽  
pp. 298-306 ◽  
Author(s):  
I.Wayne Cheney ◽  
Suhaila Naim ◽  
Vicky C.H. Lai ◽  
Shannon Dempsey ◽  
Daniel Bellows ◽  
...  
Keyword(s):  
Cell Culture ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Enzymatic Activity ◽  
Rna Replication ◽  
Viral Rna ◽  
Subgenomic Replicon ◽  
Replicon Cell ◽  
Ns5b Polymerase

Large-scale structure-activity relationship study of hepatitis C virus NS5B polymerase inhibition using SMILES-based descriptors

2015 ◽  
Vol 19 (4) ◽  
pp. 955-964 ◽  
Author(s):  
Apilak Worachartcheewan ◽  
Virapong Prachayasittikul ◽  
Alla P. Toropova ◽  
Andrey A. Toropov ◽  
Chanin Nantasenamat
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Large Scale ◽  
Large Scale Structure ◽  
Structure Activity Relationship ◽  
Scale Structure ◽  
Activity Relationship ◽  
Structure Activity ◽  
Relationship Study ◽  
Ns5b Polymerase

scholarly journals Effect of Hepatitis C Virus (HCV) NS5B-Nucleolin Interaction on HCV Replication with HCV Subgenomic Replicon

2006 ◽  
Vol 80 (7) ◽  
pp. 3332-3340 ◽  
Author(s):  
Tetsuro Shimakami ◽  
Masao Honda ◽  
Takashi Kusakawa ◽  
Takayuki Murata ◽  
Kunitada Shimotohno ◽  
...  
Keyword(s):  
Amino Acids ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nonstructural Protein ◽  
Polymerase Activity ◽  
Subgenomic Replicon ◽  
Huh7 Cells ◽  
Hcv Ns5b

ABSTRACT We previously reported that nucleolin, a representative nucleolar marker, interacts with nonstructural protein 5B (NS5B) of hepatitis C virus (HCV) through two independent regions of NS5B, amino acids 208 to 214 and 500 to 506. We also showed that truncated nucleolin that harbors the NS5B-binding region inhibited the RNA-dependent RNA polymerase activity of NS5B in vitro, suggesting that nucleolin may be involved in HCV replication. To address this question, we focused on NS5B amino acids 208 to 214. We constructed one alanine-substituted clustered mutant (CM) replicon, in which all the amino acids in this region were changed to alanine, as well as seven different point mutant (PM) replicons, each of which harbored an alanine substitution at one of the amino acids in the region. After transfection into Huh7 cells, the CM replicon and the PM replicon containing NS5B W208A could not replicate, whereas the remaining PM replicons were able to replicate. In vivo immunoprecipitation also showed that the W208 residue of NS5B was essential for its interaction with nucleolin, strongly suggesting that this interaction is essential for HCV replication. To gain further insight into the role of nucleolin in HCV replication, we utilized the small interfering RNA (siRNA) technique to investigate the knockdown effect of nucleolin on HCV replication. Cotransfection of replicon RNA and nucleolin siRNA into Huh7 cells moderately inhibited HCV replication, although suppression of nucleolin did not affect cell proliferation. Taken together, our findings strongly suggest that nucleolin is a host component that interacts with HCV NS5B and is indispensable for HCV replication.

The discovery and structure–activity relationships of pyrano[3,4-b]indole-based inhibitors of hepatitis C virus NS5B polymerase

2011 ◽  
Vol 21 (11) ◽  
pp. 3227-3231 ◽  
Author(s):  
Randy W. Jackson ◽  
Matthew G. LaPorte ◽  
Torsten Herbertz ◽  
Tandy L. Draper ◽  
Janet A. Gaboury ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Ns5b Polymerase
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