Loading ...
Sorry, an error occurred while loading the content.

Protease inhibitors for treatment of chronic hepatitis C: a new target for the magic bullet identified

Expand Messages
  • claudine intexas
    NATAP - www.natap.org Protease inhibitors for treatment of chronic hepatitis C: a new target for the magic bullet identified Journal of Hepatology, Jan 2004,
    Message 1 of 1 , Dec 17, 2003
    • 0 Attachment
      NATAP - www.natap.org

      Protease inhibitors for treatment of chronic hepatitis C: a new
      target for the magic bullet identified

      Journal of Hepatology, Jan 2004, Vol. 40 (1) (2004) pp. 184-186 Peter
      Ferenci. Division of GI/Hepatology, Vienna General Hospital (AKH),
      Univ of Vienna

      Once a virus enters the body it triggers a series of events which
      ultimately should result in the inhibition of viral replication
      and/or its elimination. The first line of host defense is the
      activation of multiple signaling cascades to produce cytokines that
      and stimulate immune responses. Interferons (IFN) are the most
      important components of the innate host defense. They are rapidly
      produced by and released from the infected cell and bind to specific
      receptors on the surface of uninfected cells. The main signaling
      pathways involve tyrosine phosphorylation and activation of signal
      transducers and activators of transcription (STAT) factors by Janus
      tyrosine kinases (JAK) at the cell membrane, followed by release of
      STAT factors and their migration to the nucleus, where they induce
      the expression of the transcription of genes that determine the
      antiviral responses like 2�-5�-oligoadenylate synthetase (OAS) or the
      IFN-inducible protein kinase (PKR) (see Fig. 1). PKR can restrict
      viral replication by phosphorylation of the protein synthesis
      initiation factor eIF2-subunit. In order to establish a chronic
      infection, the virus has to bypass host defense mechanisms. The
      interaction of HCV envelope protein E2 and PKR may be one mechanism
      by which HCV circumvents the antiviral effect of IFN.

      FIGURE 1
      [Unable to display image]

      Fig. 1. Simplified scheme of activation of type I interferons (IFNs)
      by viral infections. HCVs like most viruses have evolved strategies
      to block and interfere with the IFN pathway. (1) Blocking of IFN
      induction/expression by a serine protease in the NS3/NS4 region
      inhibits the activation of IRF-3. (2) Interaction of PKR with HCV E2
      protein abolishes antiviral activity of IFN. Abbreviations: IKK, IB
      kinase; IRF, IFN-regulatory factor; ISG, IFN-stimulated genes; JAK,
      Janus kinase; Mx, myxovirus-resistance proteins; OAS, oligoadenylate
      synthetase; PKR, IFN-inducible protein kinase; STAT, signal
      transducer and activator of transcription; TYK, tyrosine kinase.

      Recently the mechanisms which control the rapid production of IFN
      following recognition of viral antigens were intensively studied.
      Posttranslational modification of proteins like nuclear factor-B
      (NF-B) or ATF2/c-Jun, and IFN regulatory factors (IRF) 3 and 7 were
      identified as major regulators of IFN production. IRF-3 is directly
      activated after virus infection and stimulates the expression of
      /-IFN early in infection, IRF-7 then amplifies the expression of
      other IFN genes in later stages. IRFs are activated by
      phosphorylation most likely catalyzed by a virus-activated kinase
      (VAK), which requires the interaction between IRF-3 and the
      C-terminal domain of IB-kinase- (IKK) subunit of the IKK complex,
      that regulate the activation of the NF-B pathway.

      Sharma et al. identified the IKK subunit and a TANK (TRAF family
      member associated NF-B activator)-binding kinase (TBK1) as activator
      of IRF-3 and IRF-7 by phosphorylation. Expression of IKK and IRF-7
      resulted in a 2000-fold stimulation of the IRF-7 responsive IFNA4
      promoter and a 60-fold stimulation of the IFNB promoter. Further
      investigations showed that with reduced IKK and TBK1 expression
      virus-induced phosphorylation of IRF-3 was inhibited. Finally, in the
      presence of IKK and IRF-3, replication of the vesicular stomatitis
      virus was decreased by 4 logs. When mutated IRF-3 or IKK was used,
      viral replication was restored to baseline levels. These studies
      demonstrate that IKK and TBK1 are components of the VAK required for
      IRF-3 and IRF-7 phosphorylation and underlines their primary role in
      triggering an early IFN-mediated antiviral response. IKK and TBK1
      phosphorylate serine, including Ser396 on IRF-3.

      Foy et al. studied the role of the hepatitis C virus (HCV) serine
      protease for the regulation of IFR-3. They used Huh7 hepatoma cells
      to replicate HCV, genotype 1b and osteosarcoma cells to express the
      full length HCV-genotype 1a polyprotein. Infection of control cells
      with the Sendai virus induced IRF-3 activation, which was completely
      blocked in cells expressing HCV. Pretreatment of HCV producing cells
      with IFN2b-inhibited HCV replication and restored Sendai-virus
      activation of IRF3, showing that inhibition of IRF-3 was HCV specific
      and blocked the expression of IRF-3 activated genes. The inhibitory
      effect of HCV was concentration dependent. At very low-virus
      concentration HCV even induced IRF-3 phosphorylation. The strongest
      inhibition was exerted by the serine protease activity in the NS3/4A
      complex. The new serine protease inhibitor SCH6 (Schering-Plough)
      reversed the HCV-mediated inhibition of Sendai virus induced IRF-3
      phosphylation. Thus, serine protease inhibitors restore IRF-3
      activation allowing the expression of type I IFNs and an effective
      antiviral response. SCH6 not only inhibited HCV protease, but also
      allowed restoration of cellular immune response. Serine protease
      inhibitors may become important drugs in treatment for chronic
      hepatitis C. Several drug companies are working on HCV protease
      inhibitors. Farthest along is BILN 2061 from Boehringer Ingelheim
      (preliminary data were presented at the Annual AASLD meeting 2002),
      which was already tested in humans. (Editorial note: data on BILN
      2061 was presented at AASLD 2003 along with new data for SCH 7 and
      VX-950 (Vertex Pharm), two HCV protease inhibitors. Clinical studies
      for SCH 7 and VX-950 are scheduled for 2004. It appears that BILN
      2061 may not be developed due to animal toxicity but I understand
      that Boehringer Ingelheim has additional compounds to develop.



      __________________________________
      Do you Yahoo!?
      New Yahoo! Photos - easier uploading and sharing.
      http://photos.yahoo.com/
    Your message has been successfully submitted and would be delivered to recipients shortly.