Promising candidates for the treatment of chronic hepatitis C.

ABSTRACT

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.