Non-Nucleoside Benzimidazole-Based Allosteric Inhibitors of the Hepatitis C Virus NS5B Polymerase:  Inhibition of Subgenomic Hepatitis C Virus RNA Replicons in Huh-7 Cells

Beaulieu, Pierre L.; Bousquet, Yves; Gauthier, Jean; Gillard, James; Marquis, Martin; Pellerin, Charles; Valois, Serge; Kukolj, George

doi:10.1021/jm040134d

Cited by 90 publications

(55 citation statements)

References 29 publications

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“…compound A is a potent inhibitor of NS5B in vitro, the effect on HCV RNA replication in cell culture, as measured with the HCV replicon system (44), was marginal (63% inhibition at 50 M) and attributable to the poor cell permeability accorded by the acid functionalities and net negative charge of the compound (28). In an effort to identify C-5 carboxamide analogues that retained in vitro potency but demonstrated superior cell culture activity, a combinatorial chemistry approach 5 led to the discovery of compound C with an EC 50 in a 72-h replicon assay of 1.1 M. Other benzimidazoles that have demonstrated cell-based inhibition of HCV replicons have a free C-5 carboxylic acid (33), whereas compound C features a distinct C-5 carboxamide extension.…”

Section: Inhibition Of Hcv Replicons and Resistance To Benzimidazole mentioning

confidence: 99%

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Binding Site Characterization and Resistance to a Class of Non-nucleoside Inhibitors of the Hepatitis C Virus NS5B Polymerase

Kukolj

McGibbon

McKercher

et al. 2005

Journal of Biological Chemistry

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122

114

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The virally encoded NS5B RNA-dependent RNA polymerase has emerged as a prime target in the search for specific HCV antivirals. A series of benzimidazole 5-carboxamide compounds inhibit the cellular RNA replication of a HCV subgenomic replicon and we have advanced our understanding of this class of inhibitors through a combination of complementary approaches that include biochemical cross-linking experiments with a photoreactive analogue followed by mass spectrometry analysis of the enzyme. A novel binding site has been localized for these inhibitors at the junction of the thumb domain and the N-terminal finger loop. Furthermore, the isolation and characterization of resistant replicon mutants that co-localize to this region distinguished this class of compounds from other non-nucleoside NS5B inhibitors that bind to distinct allosteric sites. Resistant mutations that emerged with the benzim- More than 2% of the world population are chronically infected with hepatitis C virus (HCV), 2 a flavivirus that is the etiological agent of non-A non-B hepatitis (1, 2). A large proportion of patients fail to achieve a sustained response to current therapies consisting of a combination of pegylated interferon and ribavirin. The discovery and development of specific anti-HCV chemotherapies aims to address this unmet clinical need and has focused on inhibitors of virally encoded functions. HCV encodes a linear polyprotein of ϳ3010 amino acids that is cleaved at multiple sites by cellular and viral proteases to produce structural and non-structural (NS) proteins (for review, see Ref.3). One of the non-structural proteins, NS5B, catalyzes the RNA-dependent RNA polymerization of a negative strand intermediate and the subsequent generation of multiple copies of the plus strand viral genome; this enzyme has emerged as a principal target for chemotherapeutic inhibition of HCV replication (4).The three-dimensional structure of the NS5B polymerase reveals an organization comparable with other nucleic acid polymerases with the familiar features of fingers, palm, and thumb domains that are organized in a "right-hand" motif (5-7). A distinct feature of the HCV polymerase (and closely related RNA-dependent RNA polymerase) active site cavity is the protrusion of a unique ␤-hairpin from the thumb subdomain that apparently plays a role in the initiation of de novo RNA synthesis as demonstrated by both structural and biochemical studies (8 -11). Another additional feature of the HCV polymerase is two loops that bridge the fingers and thumb subdomain and result in an encircled active site. This feature is now known to be shared by other RNA-dependent RNA polymerase from rhinovirus, bacteriophage 6, rabbit hemorrhagic disease virus, bovine viral diarrhea virus, Norwalk virus,. Interestingly, the interface between the HCV polymerase N-terminal 1 loop and the thumb subdomain is the location of a GTP binding site (8), although its precise biological role is unsolved.A number of different HCV polymerase inhibitors have emerged that can be broadly di...

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Section: Inhibition Of Hcv Replicons and Resistance To Benzimidazole mentioning

confidence: 99%

“…Benzimidazole 5-carboxamide inhibitors have also been extensively pursued as HCV NS5B-specific inhibitors (25,(27)(28)(29)(30)35). 3 These compounds inhibit an initiation phase of the reaction, and a modified NS5B polymerase with lower RNA-substrate affinity was used to identify these compounds in a screening campaign (32).…”

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confidence: 99%

Binding Site Characterization and Resistance to a Class of Non-nucleoside Inhibitors of the Hepatitis C Virus NS5B Polymerase

Kukolj

McGibbon

McKercher

et al. 2005

Journal of Biological Chemistry

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122

114

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“…In other studies, they also can act as antibacterial agent (Nezhad et al, 2005;Ozden et al, 2005), and showed anthelmintics activity of Trichinella spiralis (Mavrova et al, 2005), anti-inflammatory and analgesic activities (Sondhi et al, 2006) and as inhibitors for the hepatitis B (Li et al, 2006) and C viruses (Beaulieu et al, 2004). Some benzimidazoles were also tested as anti-HIV (Roth et al, 1997;Smith et al, 2003), anticancer agents (Craigo et al, 1999;Rida et al, 2006) and antioxidants (Kus et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Anti-Proliferation Effects of Benzimidazole Derivatives on HCT-116 Colon Cancer and MCF-7 Breast Cancer Cell Lines

Al–Douh

Sahib²,

Osman³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Benzimidazoles 1-4 were obtained using modified synthesis methods and studied for their ability to inhibit cell proliferation of colon cancer cell HCT-116 and breast cancer cell MCF-7 using MTT assays. In the HCT-116 cell line, benzimidazole 2 was found to have an IC 50 value of 16.2±3.85 μg/mL and benzimidazole 1 a value of 28.5±2.91 μg/mL, while that for benzimidazole 4 was 24.08±0.31 μg/mL. In the MCF-7 cell line, benzimidazole 4 had an IC 50 value of 8.86±1.10 μg/mL, benzimidazole 2 a value of 30.29±6.39 μg/mL, and benzimidazole 1 a value of 31.2±4.49 μg/mL. Benzimidazole 3 exerted no cytotoxity in either of the cell lines, with IC 50 values >50 μg/mL. The results suggest that benzimidazoles derivatives may have chemotherapeutic potential for treatment of both colon and breast cancers.

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“…So by this idea in view, synthesis of fluorobenzimidazole is the interesting area of research. Interest in benzimidazole containing structure stems not only because of exhibiting broad spectrum of pharmacological activity [3] but also displaying significant activities against several viruses such as casein kinase 2 [4], factor Xa [5], hepatitis C virus [6].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, characterization, and antimicrobial activities of clubbed [1,2,4]‐oxadiazoles with fluorobenzimidazoles

Jadhav

Shaikh

Kale

et al. 2009

Journal of Heterocyclic Chem

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magnified imageIn this study, a novel series of substituted 4,6‐difluoro‐2‐{2‐[3‐(substituted‐phenyl)‐[1,2,4]‐oxadiazol‐5‐yl]‐ethyl}‐1H‐benzo[d]imidazole derivatives were synthesized by condensation of 2,4‐difluoro 6‐nitrophenyl amine with 3‐(substitutedphenyl‐[1,2,4]‐oxadiazol‐5yl) propionic acid by using 2,4,6‐trichlorobenzoyl chloride in the presence of triethyl amine base. The compounds were evaluated for their preliminary in vitro antibacterial activity against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and Salmonella typhosa. The antibacterial data of the tested compounds indicated that most of the synthesized compounds showed moderate activity with reference standard Gentamycin. J. Heterocyclic Chem., (2009).

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Non-Nucleoside Benzimidazole-Based Allosteric Inhibitors of the Hepatitis C Virus NS5B Polymerase: Inhibition of Subgenomic Hepatitis C Virus RNA Replicons in Huh-7 Cells

Cited by 90 publications

References 29 publications

Binding Site Characterization and Resistance to a Class of Non-nucleoside Inhibitors of the Hepatitis C Virus NS5B Polymerase

Binding Site Characterization and Resistance to a Class of Non-nucleoside Inhibitors of the Hepatitis C Virus NS5B Polymerase

Anti-Proliferation Effects of Benzimidazole Derivatives on HCT-116 Colon Cancer and MCF-7 Breast Cancer Cell Lines

Synthesis, characterization, and antimicrobial activities of clubbed [1,2,4]‐oxadiazoles with fluorobenzimidazoles

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