Petersen J等人发表于2008年Nature Biotechnology的文章《Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein》为乙肝治疗药物研究探索了一条新路。
全世界有3.6亿人是乙肝慢性感染患者,这些慢性肝炎可能会发展成肝硬化和肝癌(HCC)。由于现在的抗病毒治疗方法(调整机体抗病毒免疫力或抑制病毒逆转录酶)都无法达到治愈的效果,临床希望找到能在其他阶段干扰病毒复制的新策略。已有的研究《Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans》(2007 Hepatology)表明来源于大蛋白的酰化多肽在体外能阻断病毒的进入。利用人源化肝脏或树鼩肝细胞的小鼠模型进行的新研究进一步证实,大蛋白的酰化多肽在防止HBV或者绒毛猴HBV体内感染中具有可行性。这种酰化多肽能特异地在肝中富集、强大的抑制力及特殊的作用模式,使得它可以以低剂量皮下注射的方式使用。抑制乙肝病毒进入健康肝细胞成为新治疗方案,能用于防止病毒初次感染(比如肝移植后),还可以用于抑制慢性感染患者体内病毒对健康细胞的扩散传播。
________________________________________Nature Biotechnology 26, 335 - 341 (2008)
Published online: 24 February 2008 | doi:10.1038/nbt1389
Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein
Joerg Petersen1,7, Maura Dandri1,7, Walter Mier2, Marc Lütgehetmann1, Tassilo Volz1, Fritz von Weizsäcker3,6, Uwe Haberkorn2, Lutz Fischer4, Joerg-Matthias Pollok4, Berit Erbes5, Stefan Seitz5 & Stephan Urban5
360 million people are chronically infected with the human hepatitis B virus (HBV) and are consequently prone to develop liver cirrhosis and hepatocellular carcinoma. As approved therapeutic regimens—which modulate patients' antiviral defenses or inhibit the viral reverse transcriptase—are generally noncurative, strategies interfering with other HBV replication steps are required. Expanding on our demonstration that acylated peptides derived from the large HBV envelope protein block virus entry in vitro, we show their applicability to prevent HBV or woolly monkey hepatitis B virus infection in vivo, using immunodeficient urokinase-type plasminogen activator (uPA) mice repopulated with primary human or Tupaia belangeri hepatocytes. Accumulation of the peptides in the liver, their extraordinary inhibitory potency and specific mode of action permit subcutaneous delivery at very low doses. Inhibition of hepadnavirus entry thus constitutes a therapeutic approach to prevent primary HBV infection, such as after liver transplantation, and might also restrain virus spread in chronically infected patients.作者: 卢岳天 时间: 2009-8-16 12:11