Block T M, Lu X, Mehta A S, Blumberg B S, Tennant B, Ebling M, Korba B, Lansky D M, Jacob G S, Dwek R A
Viral Hepatitis Group, Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Nat Med. 1998 May;4(5):610-4. doi: 10.1038/nm0598-610.
A novel strategy for anti-viral intervention of hepatitis B virus (HBV) through the disruption of the proper folding and transport of the hepadnavirus glycoproteins is described. Laboratory reared woodchucks chronically infected with woodchuck hepatitis virus (WHV) were treated with N-nonyl-deoxynojirimycin (N-nonyl-DNJ), an inhibitor of the endoplasmic reticulum (ER) alpha-glucosidases. The woodchucks experienced significant dose dependent decreases in enveloped WHV, resulting in undetectable amounts in some cases. The reduction in viremia correlated with the levels of hyperglucosylated glycan in the serum of treated animals. This correlation supports the mechanism of action associated with the drug and highlights the extreme sensitivity of the virus to this type of glycan inhibitor. At N-nonyl-DNJ concentrations that prevented WHV secretion, the glycosylation of most serum glycoproteins appeared unaffected, suggesting great selectivity for this class of therapeutics. Indeed, this may account for the low toxicity of the compound over the treatment period. We provide the first evidence that glucosidase inhibitors can be used in vivo to alter specific steps in the N-linked glycosylation pathway and that this inhibition has anti-viral effects.
本文描述了一种通过破坏嗜肝DNA病毒糖蛋白的正确折叠和转运来进行乙型肝炎病毒（HBV）抗病毒干预的新策略。用内质网（ER）α-葡萄糖苷酶抑制剂N-壬基-脱氧野尻霉素（N-nonyl-DNJ）治疗实验室饲养的慢性感染土拨鼠肝炎病毒（WHV）的土拨鼠。土拨鼠体内包膜化的WHV出现显著的剂量依赖性减少，在某些情况下导致无法检测到。病毒血症的降低与治疗动物血清中高糖基化聚糖的水平相关。这种相关性支持了与该药物相关的作用机制，并突出了病毒对这类聚糖抑制剂的极端敏感性。在阻止WHV分泌的N-壬基-DNJ浓度下，大多数血清糖蛋白的糖基化似乎未受影响，表明这类疗法具有高度选择性。事实上，这可能解释了该化合物在治疗期间毒性较低的原因。我们提供了首个证据，表明葡萄糖苷酶抑制剂可在体内用于改变N-连接糖基化途径中的特定步骤，且这种抑制具有抗病毒作用。
