Antiviral Efficacy upon Administration of a HepDirect Prodrug of 2′-C-Methylcytidine to Hepatitis C Virus-Infected Chimpanzees
Antiviral Efficacy upon Administration of a HepDirect Prodrug of 2′-C-Methylcytidine to Hepatitis C Virus-Infected Chimpanzees
复制标题
DOI：
10.1128/aac.01152-10
复制
发表时间：
2011-08-01
影响因子：
4.9
通讯作者：
Erion, Mark D.
中科院分区：
文献类型：
--
作者：
Carroll, Steven S.;Koeplinger, Kenneth;Erion, Mark D.
据估计，全世界有1.7亿人感染丙型肝炎病毒，目前的护理标准是聚乙二醇化干扰素和利巴韦林的组合，在实现持续病毒应答方面有效，接近50%的接受治疗的患者。正在研究的新疗法包括使用病毒RNA依赖的RNA聚合酶的核苷类似物抑制剂。NM283是一种2‘-C-甲基胞苷的3’-瓦酯前药，已在丙型肝炎病毒感染患者中显示出抗病毒效果(N.Afdhal等人，J.46.补充1]：S5,2007；N.Afdhal等人，J.Hepatol。44.[补充2]：S19,2006)。提高2‘-C-甲基胞苷抗病毒效果的一种方法是增加感染肝细胞中活性抑制物5’-三磷酸的浓度。HepDirect前药技术可以通过将核苷一磷酸引入细胞内来增加肝细胞内核苷三磷酸的浓度，从而绕过通常是限速的初始激酶步骤。对口服给药后大鼠肝脏中2‘-C-甲基胞苷三磷酸水平的筛选表明，1-[3，5-二氟苯基]-1，3-丙二醇是一种有效的前药修饰。为了确定体内的抗病毒效果，该前药分别通过口服和静脉给药给两只感染丙型肝炎病毒的黑猩猩。口服和静脉注射后循环病毒载量分别下降了1.4个对数(10)IU/ml和3.6个对数(10)IU/ml。病毒载量在给药结束后反弹到给药前的水平。结果表明，在给予前药后，可以获得强大的抗病毒反应。
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.