Myrcludex在2014 APASL STC第四HBV会议

StephenW

Entry inhibitors for the treatment of acute and chronic hepatitis B and hepatitis D virus infections.
Stephan Urban
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg

For almost three decades after the discovery of Hepatitis B Virus (HBV) the early events of infection (attachment, receptor binding and fusion) remained entirely unresolved. Although the extraordinary hepatotropism of HBV and its peculiar host specificity were supposed to be linked to specific receptor binding, it remained unclear which determinant(s) within the viral envelope protein(s) are essential for mediating HBV and Hepatitis D Virus entry and which cellular receptor(s) are addressed. One reason was the lack of suitable in vitro infection systems. Following the establishment of the susceptible HepaRG cell line and primary hepatocytes from humans (PHH) as reliable cell culture infection systems, systematic analyses allowed the identification of a myristoylated preS1-subdomain as essential for specific hepatocyte binding. Using two different approaches sodium taurocholate co-transporting polypeptide (NTCP/
SCL10A1) could recently be identified as this highly specific hepatic receptor for the myristoylated preS1 subdomain. The identification of peptidic ligands of this receptor acting as potent inhibitors of viral entry opened a novel therapeutic option to prevent infection and treat chronically infected patients. The lead substance of such a NTCP-ligand (Myrcludex B) displayed remarkable liver tropism and inhibitory potential at picomolar concentrations. Following proof of principal studies
in HBV and HDV mouse models Myrcludex B was transferred into clinical development and successfully passed a phase Ia clinical safety trial in 2013. Following these initial safety studies Myrcludex entered two phase IIa efficacy trials in chronically HBV and HBV/HDV co-infected patients, which are currently running. Interim results of these still ongoing clinical trials show safety in all applied doses and remarkable virologic and biochemic effects in both HBV and HBV/HDV
infected patients. As expected from targeting NTCP, bile salt levels are influenced by Myrcludex B therapy. In addition to its direct action resulting in in vivo inactivation of HBV receptor function Myrcludex B administration induced HBV-preS-specific antibody responses that might contribute to a sustained suppression of de novo infection following Myrcludex B withdrawal. Thus entry
inhibition, in addition to its expected preventive effects, has been demonstrated to be effective in chronically HBV and HDV infected patients and might contribute as one important pile in future curative therapeutic regimens for both viruses.

StephenW

进入抑制剂用于治疗急性和慢性乙型肝炎和丁型肝炎病毒感染的治疗。
斯蒂芬城市
传染病科，分子病毒学，大学医院海德堡

对于乙肝病毒（HBV）感染（附件，受体结合和融合）的早期事件后发现，几乎三十年仍然完全没有得到解决。尽管HBV和其特有的宿主特异性的非凡嗜肝被认为链接到特定的受体结合，但仍不清楚哪个行列式（多个）病毒包膜蛋白（多个）内的是必不可少调解HBV和丁型肝炎病毒进入和哪个蜂窝受体（S）的处理。其中一个原因是缺乏合适的体外感染系统。成立后易感HepaRG细胞系和原代肝细胞由人类（PHH），为可靠的细胞培养感染的系统，系统的分析允许肉豆蔻酰化前S1子域为特定的肝细胞结合作为必要的识别。使用两种不同的方法牛磺胆酸钠共转运多肽（NTCP/
SCL10A1）最近也被认定为这一高度特异性受体肝为肉豆蔻前S1子。这种受体的配体肽作用病毒进入作为强效抑制剂的鉴定开辟了一种新的治疗选择，以防止感染和治疗慢性感染的患者。这样的NTCP配位体（Myrcludex B）的铅物质显示显着的肝脏趋向性和抑制性潜力在皮摩尔浓度。主要研究以下证明
在HBV和HDV小鼠模型Myrcludex B被转移到临床开发，并成功地通过一个阶段IA临床安全性试验在2013年继Myrcludex输入了两个IIa期有效性试验在慢性HBV和HBV/ HDV合并感染的患者，这些最初的安全性研究，当前正在运行。这些仍在进行临床试验的中期业绩显示安全性在所有的应用剂量和显着的病毒学和biochemic效应在这两个HBV和HBV/ HDV
受感染的病人。正如预期的那样，从目标NTCP，胆盐水平由Myrcludex B治疗的影响。除了其导致体内失活的HBV受体功能Myrcludex乙给药诱导的HBV-的preS-特异性抗体应答可能有助于从头感染以下Myrcludex乙撤回持续抑制直接行动。因此进入
抑制，除了其预期预防效果，已被证明是有效的慢性HBV和HDV感染的患者和可能为一个重要的桩在未来治疗治疗方案对于两种病毒贡献。

咬牙硬挺

效果还行？

StephenW

回复 咬牙硬挺 的帖子

Myrcludex诱导HBV-的preS-特异性抗体应答, 可能有助于Myrcludex停止用药后持续抑制再感染

重韧

也是研究的时间够长了，看起来也就理论上比核苷类的好些，功能性治愈的目标达不到。

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