Allosteric inhibition of the hepatitis C virus NS5B RNA dependent RNA polymerase.
The human and monetary costs of chronic hepatitis C and the complications arising from this disease emphasize the urgency to find a treatment for Hepatitis C Virus (HCV) infected patients. The current standard of treatment for patients chronically infected with HCV is combination therapy with pegylated interferon plus ribavirin. Recently, viral enzymes have become the target of efforts to develop small molecule inhibitors interfering with the essential steps in the life cycle of the virus. Amongst these enzymes the HCV-encoded NS5B RNA-dependent RNA polymerase (NS5B RdRp) is essential for viral replication and has been recognized as a prime target for therapeutic intervention. Several distinct classes of inhibitors of NS5B RdRp have been disclosed in the literature, including active site inhibitors such as nucleosides and pyrophosphate mimetics, as well as non-nucleoside inhibitors. The latter, based on the success of allosteric inhibitors in the treatment of HIV infection, have been developed into compounds which show activity in the subgenomic cell-culture assay of HCV replication. This review provides an account of the recent developments in this field.
Koch
Uwe
U
Istituto di Ricerche di Biologia Molecolare P. Angeletti S.P.A. -- Merck Research Laboratories, Rome, Via Pontina km 30,600, 00040 Pomezia (Rome), Italy.
Narjes
Frank
F
D000179:Acrylates / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010649:Phenylalanine / Q000494:pharmacology; D011487:Protein Conformation; D011759:Pyrrolidines / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000179:Acrylates; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D017361:Viral Nonstructural Proteins; D010649:Phenylalanine; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase