HCV796: A selective nonstructural protein 5B polymerase inhibitor with potent anti-hepatitis C virus activity In Vitro, in mice with chimeric human livers, and in humans infected with hepatitis C virus

Abstract

Anti-hepatitis C virus (HCV) drug development has been challenged by a lack of experience with inhibitors inclusive of in vitro, animal model, and clinical study. This manuscript outlines activity and correlation across such a spectrum of models and into clinical trials with a novel selective nonstructural protein 5B (NS5B) polymerase inhibitor, HCV796. Enzyme assays yielded median inhibitory concentration ( H epatitis C virus (HCV) infects an estimated 170 million people across the world, 1 with substantial risk of severe chronic liver disease, cirrhosis, and hepatocellular cancer. 2,3 Standard therapy with pegylated interferon and ribavirin clears virus in only half of those treated, is associated with significant treatment-related morbidity, and is cost-prohibitive in much of the world. 4,5 HCV is the leading indication for liver transplantation across the developed world. Despite intensive effort, no new drugs have been approved for therapy in the last decade. More effective and less toxic anti-HCV therapeutics as well as preventive vaccines are greatly needed. A major challenge with development of anti-HCV drugs has been the lack of in vitro, animal model, and clinical experience with inhibitors. Although correlation exists for interferon, there are limited data for molecules with novel mechanisms. The goal of the current work was to delineate the activity of a selective nonstructural protein 5B (NS5B) polymerase inhibitor in vitro by enzyme assay and in the replicon, in vivo in the chimeric mouse model, and in patients infected with HCV.Abbreviations: EC 50 , half maximal effective concentration; hAAT, Human ␣-1 antitrypsin; HCV, hepatitis C virus; IC 50 , median inhibitory concentration; IFN, interferon; NS5B, nonstructural protein 5B; pegylated interferon; RdRp, SCID, severe combined immunodeficiency; uPA, urokinase plasminogen activator. From

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Experimental models for hepatitis C viral infection

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