Antiviral Efficacy upon Administration of a HepDirect Prodrug of 2 '-C-Methylcytidine to Hepatitis C Virus-Infected Chimpanzees

作者：Carroll Steven S^*; Koeplinger Kenneth; Vavrek Marissa; Zhang Nanyan Rena; Handt Laurence; MacCoss Malcolm; Olsen David B; Reddy K Raja; Sun Zhili; van Poelje Paul D; Fujitaki James M; Boyer Serge H; Linemeyer David L; Hecker Scott J; Erion Mark D

来源：Antimicrobial Agents and Chemotherapy, 2011, 55(8): 3854-3860.

DOI：10.1128/AAC.01152-10

Hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide, and the current standard of care, a combination of pegylated interferon alpha and ribavirin, is efficacious in achieving sustained viral response in similar to 50% of treated patients. Novel therapies under investigation include the use of nucleoside analog inhibitors of the viral RNA-dependent RNA polymerase. NM283, a 3'-valyl ester prodrug of 2'-C-methylcytidine, has demonstrated antiviral efficacy in HCV-infected patients (N. Afdhal et al., J. Hepatol. 46[Suppl. 1]:S5, 2007; N. Afdhal et al., J. Hepatol. 44[Suppl. 2]:S19, 2006). One approach to increase the antiviral efficacy of 2'-C-methylcytidine is to increase the concentration of the active inhibitory species, the 5'-triphosphate, in infected hepatocytes. HepDirect prodrug technology can increase intracellular concentrations of a nucleoside triphosphate in hepatocytes by introducing the nucleoside monophosphate into the cell, bypassing the initial kinase step that is often rate limiting. Screening for 2'-C-methylcytidine triphosphate levels in rat liver after oral dosing identified 1-[3,5-difluorophenyl]-1,3-propandiol as an efficient prodrug modification. To determine antiviral efficacy in vivo, the prodrug was administered separately via oral and intravenous dosing to two HCV-infected chimpanzees. Circulating viral loads declined by similar to 1.4 log(10) IU/ml and by >3.6 log(10) IU/ml after oral and intravenous dosing, respectively. The viral loads rebounded after the end of dosing to predose levels. The results indicate that a robust antiviral response can be achieved upon administration of the prodrug.

• 出版日期2011-8