Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients

Hinrichsen, Holger; Benhamou, Yves; Wedemeyer, Heiner; Reiser, Markus; Sentjens, Roel E.; Calleja, José Luís; Forns, Xavier; Erhardt, Andreas; Crönlein, Jens; Chaves, Ricardo L.; Yong, Chan‐Loi; Nehmiz, Gerhard; Steinmann, Gerhard

doi:10.1053/j.gastro.2004.08.002

Cited by 326 publications

(233 citation statements)

References 29 publications

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“…These efforts, conducted in parallel by several pharmaceutical companies, led to the discovery of many protease inhibitors. Proof-of-concept for the successful clinical activity of this drug class was first demonstrated by the macrocyclic inhibitor BILN-2061 (Boehringer Ingelheim) (20,21), which was later dropped from clinical trials in 2006 due to cardiotoxicity (22). Many other NS3/4A protease inhibitors are currently in development, and telaprevir (Vertex), boceprevir (Schering-Plough), and ITMN-191 (Intermune) lead the way in advanced phases of human clinical trials (Fig.…”

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confidence: 99%

Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding

Romano

Ali

Royer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

181

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Hepatitis C virus infects an estimated 180 million people worldwide, prompting enormous efforts to develop inhibitors targeting the essential NS3/4A protease. Resistance against the most promising protease inhibitors, telaprevir, boceprevir, and ITMN-191, has emerged in clinical trials. In this study, crystal structures of the NS3/4A protease domain reveal that viral substrates bind to the protease active site in a conserved manner defining a consensus volume, or substrate envelope. Mutations that confer the most severe resistance in the clinic occur where the inhibitors protrude from the substrate envelope, as these changes selectively weaken inhibitor binding without compromising the binding of substrates. These findings suggest a general model for predicting the susceptibility of protease inhibitors to resistance: drugs designed to fit within the substrate envelope will be less susceptible to resistance, as mutations affecting inhibitor binding would simultaneously interfere with the recognition of viral substrates.drug design | hepatitis C | substrate envelope D rug resistance is a major obstacle in the treatment of quickly evolving diseases. Hepatitis C virus (HCV) is a genetically diverse Hepacivirus of the Flaviviridae family infecting an estimated 180 million people worldwide (1). The viral RNA genome is translated as a single polyprotein and subsequently processed by host-cell and viral proteases into structural (C, E1, E2, and p7) and nonstructural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) proteins (2). The viral RNA-dependent RNA polymerase, NS5B, is inherently inaccurate and misincorporation of bases accounts for a very high mutation rate (3). While some mutations are neutral, others will alter the viability of the virus and propagate with varying efficiencies in each patient. Thus HCV infected individuals will develop a heterogeneous population of virus variants known as quasispecies (4). As patients begin treatment, the selective pressures of antiviral drugs will favor drug resistant variants (5). Therefore, an inhibitor must not only recognize one protein variant, but an ensemble of related enzymes. A detailed understanding of the atomic mechanisms of resistance is essential to effectively combat drug resistance against HCV antivirals.The essential HCV NS3/4A protease is an attractive therapeutic target responsible for cleaving at least four sites along the viral polyprotein. These sites share little sequence homology except for an acid at position P6, Cys or Thr at P1, and Ser or Ala at P1′ (Table S1). The first cleavage event at the 3-4A junction occurs in cis as a unimolecular process, while the remaining substrates are processed bimolecularly in trans. The NS3/4A protease also cleaves the human cellular targets TRIF and MAVS, which confounds the innate immune response to viral infection (6-8).Early drug design efforts were hampered by the relatively shallow, featureless architecture of the protease active site. The eventual observation of N-terminal product inhibition served as a stepping stone f...

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Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding

Romano

Ali

Royer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

181

244

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“…Several new HCV protease and polymerase inhibitors are under investigation in clinical studies and may become approved in the near future. [46][47][48][49] Kinetic analyses of monotherapy or combination therapy with new drugs that are designed to specifically inhibit viral enzymes with or without interferon can be used to compare efficacy of these new treatments with that of existing interferon-based treatments. A kinetic analysis of the serine protease inhibitor BILN 2061 demonstrated that the effectiveness in blocking viral production was dose-dependent and high compared with interferon-␣.…”

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New kinetic models for the hepatitis C virus

et al. 2005

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K inetic models of hepatitis C virus (HCV) RNA decay induced by interferon (IFN) therapy have been developed by us and others. [1][2][3][4][5][6] The models, inspired by previous work on HIV and hepatitis B virus kinetics, 7-9 stimulated the collection of frequent viral loads and alanine aminotransferase (ALT) measurements after the initiation of therapy that revealed previously unknown kinetic patterns of HCV RNA change. The models have successfully summarized much of these new kinetic data and have given insights into features of HCV biology in vivo, such as the rate of virion clearance and the daily rate of virion production. More importantly from a clinical perspective, the models have allowed quantification of the antiviral effects of therapy and thus have made comparison of the antiviral effectiveness of different drug regimens possible using data collected over short intervals.

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“…Other in vitro studies have shown that ITMN-191 displays synergistic antiviral activity in combination with interferon [35,36] , as well as HCV polymerase inhibitor R1479 [37] . Recently, the clinical trials for BILB2061, another specific and potent inhibitor of HCV NS3 protease, were halted due to drug-induced cardiotoxicity [38] . ACH-806 is a novel anti-HCV agent, cur rently in phase Ⅰ/Ⅱ clinical studies, which has a distinct m e c h a n i s m o f a c t i o n .…”

Section: Protease Inhibitorsmentioning

confidence: 99%

Specifically targeted antiviral therapy for hepatitis C virus

Parfieniuk¹

2007

WJG

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Hepatitis C virus (HCV) infection affects 180 million people worldwide with the predominant prevalence being infection with genotype 1, followed by genotypes 2 and 3. Standard anti-HCV therapy currently aims to enhance natural immune responses to the virus, whereas new therapeutic concepts directly target HCV RNA and viral enzymes or influence host-virus interactions. Novel treatment options now in development are focused on inhibitors of HCVspecific enzymes, NS3 protease and NS5B polymerase. These agents acting in concert represent the concept of specifically targeted antiviral therapy for HCV (STAT-C). STAT-C is an attractive strategy in which the main goal is to increase the effectiveness of antiviral responses across all genotypes, with shorter treatment duration and better tolerability. However, the emergence of resistant mutations that limit the use of these compounds in monotherapy complicates the regimens. Thus, a predictable scenario for HCV treatment in the future will be combinations of drugs with distinct mechanisms of action. For now, it seems that interferon will remain a fundamental component of any new anti-HCV therapeutic regimens in the near future; therefore, there is pressure to develop forms of interferon that are more effective, less toxic, and more convenient than pegylated interferon.

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Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients

Cited by 326 publications

References 29 publications

Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding

Drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding

New kinetic models for the hepatitis C virus

Specifically targeted antiviral therapy for hepatitis C virus

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