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Author

Pierre L. Beaulieu

Bio: Pierre L. Beaulieu is an academic researcher from Boehringer Ingelheim. The author has contributed to research in topics: Hepatitis C virus & Polymerase. The author has an hindex of 36, co-authored 133 publications receiving 4640 citations.


Papers
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Journal ArticleDOI
13 Nov 2003-Nature
TL;DR: Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor, illustrating the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.
Abstract: Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.

895 citations

Patent
07 Feb 2007
TL;DR: An enantiomer, diastereoisomer or tautomer of a compound, represented by formula I: wherein A, B, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as defined herein, or a salt or ester thereof, as an inhibitor of HCV NS5B polymerase.
Abstract: An enantiomer, diastereoisomer or tautomer of a compound, represented by formula I: wherein A, B, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as defined herein, or a salt or ester thereof, as an inhibitor of HCV NS5B polymerase.

379 citations

Journal ArticleDOI
TL;DR: In this article, a mixture of a 1,2-phenylenedi-amine and an aldehyde in wet DMF at room temperature is used to synthesize benzimidazoles.
Abstract: Addition of oxone ® to a mixture of a 1,2-phenylenedi- amine and an aldehyde in wet DMF at room temperature results in rapid formation of benzimidazoles under very mild conditions. The reaction is applicable to a wide range of substrates including ali- phatic, aromatic and heteroaromatic aldehydes, and is not signifi- cantly affected by steric or electronic effects. In most cases, crude products are isolated in good to excellent yields (59-95%) and ho- mogeneities (86-99%) by simple precipitation or extraction from the reaction mixture and do not require additional purification. Lim- itations to the scope of this methodology were encountered in cases where aldehydes were sensitive to oxone ® under the acidic reaction conditions. The features of this methodology make it particularly well suited for the high-throughput, solution-phase synthesis of benzimidazole libraries. The low cost and simplicity of this proce- dure makes it equally attractive for preparative-scale syntheses where safety and environmental issues are of greater concern.

201 citations

Journal ArticleDOI
TL;DR: A novel class of compounds and unique binding site expand the diversity of HCV antivirals currently under development and offer the potential to improve the treatment of chronic HCV infection.

130 citations

Journal ArticleDOI
15 Dec 1994-Nature
TL;DR: BILD 1263 is reported on, which to the authors' knowledge is the first HSV RNR subunit-association inhibitor with antiviral activity in vivo and may lead to the design of new strategies to treat herpesvirus infections in humans.
Abstract: Herpes simplex viruses (HSV) types 1 and 2 encode their own ribonucleotide reductases (RNRs) (EC 1.17.4.1) to convert ribonucleoside diphosphates into the corresponding deoxyribonucleotides. Like other iron-dependent RNRs, the viral enzyme is formed by the reversible association of two distinct homodimeric subunits. The carboxy terminus of the RNR small subunit (R2) is critical for subunit association and synthetic peptides containing these amino-acid sequences selectively inhibit the viral enzyme by preventing subunit association. Increasing evidence indicates that the HSV RNR is important for virulence and reactivation from latency. Previously, we reported on the design of HSV RNR inhibitors with enhanced inhibitory potency in vitro. We now report on BILD 1263, which to our knowledge is the first HSV RNR subunit-association inhibitor with antiviral activity in vivo. This compound suppresses the replication of HSV-1, HSV-2 and acyclovir-resistant HSV strains in cell culture, and also strongly potentiates the antiviral activity of acyclovir. Most importantly, its anti-herpetic activity is shown in a murine ocular model of HSV-1-induced keratitis, providing an example of potent nonsubstrate-based antiviral agents that prevent protein-protein interactions. The unique antiviral properties of BILD 1263 may lead to the design of new strategies to treat herpesvirus infections in humans.

122 citations


Cited by
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Journal ArticleDOI
TL;DR: GOLD (Genetic Optimisation for Ligand Docking) is an automated ligand docking program that uses a genetic algorithm to explore the full range of ligand conformational flexibility with partial flexibility of the protein, and satisfies the fundamental requirement that the ligand must displace loosely bound water on binding.

5,882 citations

Journal ArticleDOI
20 Oct 2005-Nature
TL;DR: Cardif is described, a new CARD-containing adaptor protein that interacts with RIG-I and recruits IKKα, IKKβ and IKKɛ kinases by means of its C-terminal region, leading to the activation of NF-κB and IRF3.
Abstract: Antiviral immunity against a pathogen is mounted upon recognition by the host of virally associated structures. One of these viral 'signatures', double-stranded (ds) RNA, is a replication product of most viruses within infected cells and is sensed by Toll-like receptor 3 (TLR3) and the recently identified cytosolic RNA helicases RIG-I (retinoic acid inducible gene I, also known as Ddx58) and Mda5 (melanoma differentiation-associated gene 5, also known as Ifih1 or Helicard). Both helicases detect dsRNA, and through their protein-interacting CARD domains, relay an undefined signal resulting in the activation of the transcription factors interferon regulatory factor 3 (IRF3) and NF-kappaB. Here we describe Cardif, a new CARD-containing adaptor protein that interacts with RIG-I and recruits IKKalpha, IKKbeta and IKKvarepsilon kinases by means of its C-terminal region, leading to the activation of NF-kappaB and IRF3. Overexpression of Cardif results in interferon-beta and NF-kappaB promoter activation, and knockdown of Cardif by short interfering RNA inhibits RIG-I-dependent antiviral responses. Cardif is targeted and inactivated by NS3-4A, a serine protease from hepatitis C virus known to block interferon-beta production. Cardif thus functions as an adaptor, linking the cytoplasmic dsRNA receptor RIG-I to the initiation of antiviral programmes.

2,328 citations

Journal ArticleDOI
22 Jul 2005-Science
TL;DR: A full-length HCV genome that replicates and produces virus particles that are infectious in cell culture (HCVcc) is described, suggesting that this in vitro system will aid in the search for improved antiviral compounds.
Abstract: Many aspects of the hepatitis C virus (HCV) life cycle have not been reproduced in cell culture, which has slowed research progress on this important human pathogen. Here, we describe a full-length HCV genome that replicates and produces virus particles that are infectious in cell culture (HCVcc). Replication of HCVcc was robust, producing nearly 10(5) infectious units per milliliter within 48 hours. Virus particles were filterable and neutralized with a monoclonal antibody against the viral glycoprotein E2. Viral entry was dependent on cellular expression of a putative HCV receptor, CD81. HCVcc replication was inhibited by interferon-alpha and by several HCV-specific antiviral compounds, suggesting that this in vitro system will aid in the search for improved antivirals.

2,305 citations

Journal ArticleDOI
TL;DR: Current available monotherapies-interferon, lamivudine, and adefovir dipivoxil-very rarely eradicate the virus, but greatly reduce its replication, necroinflammatory histological activity, and progression of fibrosis.

1,813 citations