Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic hepatitis C virus (HCV) infection is the cause of an emerging global pandemic of chronic liver disease. Current pegylated IFN-alpha/ribavirin combination therapies are merely 54 - 56% efficacious and are often poorly tolerated. Popular strategies to improve upon existing therapies include efforts to decrease the dosing regime, improve the safety profile and specifically target the liver, the site of HCV replication. A clear goal of novel therapies is to significantly improve the therapeutic response for HCV-infected patients. One popular scheme to accomplish this is to directly target the viral enzymes involved in HCV RNA replication. While peptidomimetics have been pursued as potent and specific inhibitors of the serine protease, nucleoside analogues and non-nucleoside small molecules have been explored as RNA-dependent RNA polymerase inhibitors with promising potential. Advances in the understanding of HCV replication at the molecular level that stem from the use of the subgenomic replicon system, in vitro enzyme assays and from co-crystallographic structure solutions of the replication enzymes with novel inhibitors have propelled these compounds into clinical development. As these candidates are developed further, there is great hope for a cure for all those chronically infected with HCV.
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PMID:Promising candidates for the treatment of chronic hepatitis C. 1288 16

Chronic hepatitis C virus (HCV) infection is the leading cause of chronic liver disease. Current therapy using pegylated interferon-alpha with ribavirin is poorly tolerated and confers an overall sustained virological response around 56%. Compounds exhibiting an improved safety profile with similar or enhanced antiviral properties may represent future treatment options. Several drug discovery programmes are ongoing to directly target the viral enzymes involved in HCV replication. Recent clinical success using a peptidomimetic inhibitor of the viral serine protease has demonstrated proof-of-concept for the use of direct antiviral agents in reducing viral load. The RNA-dependent RNA polymerase (RdRp) of HCV is also required for viral RNA replication and thus represents an attractive drug discovery target. Preclinical characterization of several non-nucleoside inhibitors (NNIs) of the HCV RdRp have been described, including a promising series of benzothiadiazine derivatives which have been shown to efficiently block viral RNA synthesis in HCV replicon cell systems. Herein, the antiviral activity, mode of action, resistance profiling and therapeutic potential of the benzothiadiazine class of compounds for clinical development are explored.
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PMID:Non-nucleoside inhibitors of the HCV polymerase. 1519 19

Chronic hepatitis C virus (HCV) infection remains a global health concern with nearly 200 million carriers worldwide. Present treatment consists of the use of pegylated interferon plus the purine analogue ribavirin. Serious side effects and the fact that an overall 40-50% of patients do not accomplish sustained virological response with the present treatment warrant the need for novel anti-HCV therapies. The HCV serine protease and the RNA-dependent RNA polymerase have shown to be excellent targets for selective antiviral therapy. Early clinical studies have resulted in encouraging results. However, and not unexpectedly, preclinical evidence suggests that the virus may become rapidly resistant to such inhibitors. Therefore, combination therapy of drugs with different mode of action and resistance profiles may be required. This review focuses on the present status of these two families of HCV inhibitors that are in development.
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PMID:Novel protease and polymerase inhibitors for the treatment of hepatitis C virus infection. 1768 67

Chronic hepatitis C virus (HCV) infection remains a global health threat with approximately 175 million carriers worldwide. Currently, treatment consists of pegylated interferon alpha plus ribavirin for 12-72 weeks, depending on HCV genotype, baseline viral load, and initial virological response to therapy. Serious adverse effects and limited sustained virological responses with this therapy warrant the need for novel HCV therapies. Specifically targeted antiviral therapies designed to inhibit the HCV serine protease and the RNA-dependent RNA polymerase have recently entered clinical development. Herein, the main characteristics of these new antiviral agents and the most important challenges arising with their use--namely, toxicities and rapid selection of resistance--are discussed.
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PMID:New therapies for hepatitis C virus infection. 1912 67

The Flaviviridae family comprises the genus Flavivirus, Hepacivirus and Pestivirus. These viruses are responsible for considerable human and animal disease and mortality worldwide. Flaviviruses cause a range of acute febrile illnesses along with encephalitic or haemorrhagic diseases. Chronic hepatitis C virus (HCV) infection is the most important hepacivirus human disease and remains a global health threat with nearly 200 million carriers worldwide. Current treatment consists in the use of peginterferon alfa (pegIFN) plus ribavirin (RBV) for 24 to 72 weeks, depending on HCV genotype, baseline viral load and the achievement of rapid virological response during therapy. However, current hepatitis C therapy fails to eradicate HCV in nearly half of treated patients and is hampered by relatively serious adverse events. No effective antiviral therapy is currently available for the treatment of flaviviruses or pestiviruses. Following the relative success of antiretroviral therapy against HIV infection, rapid progresses have been made in the development of specifically targeted antiviral therapies against HCV (STAT-C) and other Flaviviridae agents. Drug discovery for HCV is currently particularly exciting, since inhibitors of the HCV serine protease and the RNA-dependent RNA polymerase have recently entered the late stages of clinical development.
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PMID:New drug targets for hepatitis C and other Flaviviridae viruses. 1927 2