Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery and preliminary SAR of benzimidazole derivatives

Beaulieu, Pierre L.; Bös, Michael; Bousquet, Yves; Fazal, Gulrez; Gauthier, Jean; Gillard, James; Goulet, Sylvie; LaPlante, Steven R.; Poupart, Marc‐André; Lefèbvre, Sylvain; McKercher, Ginette; Pellerin, Charles; Austel, Volkhard; Kukolj, George

doi:10.1016/j.bmcl.2003.10.023

Cited by 113 publications

(73 citation statements)

References 13 publications

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“…One possible interpretation is that only the right-hand side carboxamide appendage interacts with these residues of the binding site. Notably, the right-hand side extension of these inhibitors tolerates a higher degree of chemical diversity than the core (27,29); consequently, changes in the amino acids of the binding pocket that constitute the recognition elements for this appendage may have less of an effect on inhibitor potency than substitutions that affect core recognition. The observation that the various Pro 496 and Val 499 mutations only shifted compound C potency 10 -25-and 2-3-fold, respectively (and less than 4-fold with compound A), is consistent with this interpretation.…”

Section: Discussionmentioning

confidence: 99%

“…The Pro 495 changes previously found with the benzimidazole carboxylates and now with our carboxamide analogues suggests that a structural feature, shared by both series of compounds, interacts with Pro 495 . The benzimidazole-cyclohexyl core is common to these inhibitors and tolerates few changes without significant loss in inhibitor potency (27). Hence, the ; the remaining plates depict colonies that were selected with a dual combination of BILN 2061 and compound C at the indicated concentrations derived from the matrix.…”

Section: Discussionmentioning

confidence: 99%

“…This series of compounds are being actively pursued as potential therapies for the treatment of chronic HCV infection and although progress has been made in characterizing their mechanism of action, little is known about their physical binding site or pocket (33). Based on the accumulated structure-activity relationship with this class of inhibitors, we have shown that the compounds tolerate extensive substitutions off the left-hand side imidazole portion without significantly affecting their inhibition of NS5B (27). The tolerability for substitutions at the C-2 position was exploited to prepare compound B, a potent (IC 50 0.63 M) derivative that incorporated a tethered photoreactive benzophenone moiety.…”

Section: Expression and Purification Of Recombinant Proteins From Escmentioning

confidence: 99%

“…1) were prepared according to published procedures (29,34,35). 3,4 BILN 2061 was synthesized by the medicinal chemistry group of Boehringer Ingelheim (Canada) Ltd., R&D Division (37).…”

Section: Methodsmentioning

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%

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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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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Expression and Purification Of Recombinant Proteins From Escmentioning

confidence: 99%

“…1) were prepared according to published procedures (29,34,35). 3,4 BILN 2061 was synthesized by the medicinal chemistry group of Boehringer Ingelheim (Canada) Ltd., R&D Division (37).…”

Section: Methodsmentioning

confidence: 99%

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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Antiviral Drug Discovery

Meanwell¹,

D’Andrea²,

Cianci³

et al. 2013

Drug Discovery

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Binding Mode Determination of Benzimidazole Inhibitors of the Hepatitis C Virus RNA Polymerase by a Structure and Dynamics Strategy

et al. 2004

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Eine neuartige Strategie, die NMR‐Spektroskopie, medizinische Chemie und Molecular Modeling umfasst, diente zur Bestimmung der Bindungsweise von Liganden und der Rolle ihrer Substituenten dabei. Diese erste Lösungsstruktur eines an die Hepatitis‐C‐Virus(HCV)‐Polymerase gebundenen Inhibitors (siehe Bild) liefert wertvolle Informationen für das rationale Design potenzieller Wirkstoffe gegen HCV‐Infektionen.

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Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase: discovery and preliminary SAR of benzimidazole derivatives

Cited by 113 publications

References 13 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

Antiviral Drug Discovery

Binding Mode Determination of Benzimidazole Inhibitors of the Hepatitis C Virus RNA Polymerase by a Structure and Dynamics Strategy

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