Effects of purine nucleoside analogues with a cyclobutane ring and erythromycin A oxime derivatives on duck hepatitis B virus replication in vivo and in cell culture and HIV-1 in cell culture.
Effects of purine nucleoside analogues with a cyclobutane ring and erythromycin A oxime derivatives on duck hepatitis B virus replication in vivo and in cell culture and HIV-1 in cell culture.
复制标题
带环丁烷环的嘌呤核苷类似物和红霉素A肟衍生物对鸭乙型肝炎病毒体内和细胞培养物复制以及细胞培养物中HIV-1的影响。
DOI：
10.1002/jmv.1890350307
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发表时间：
1991
影响因子：
12.7
通讯作者：
Robinson,WS
中科院分区：
文献类型：
--
作者：
Hung,LF;Brumbaugh,AE;Bhatia,G;Marion,PL;Hung,PP;Norbeck,DW;Plattner,JJ;Robinson,WS
描述了先前未针对嗜肝DNA病毒进行测试的两类化合物的特定类似物对鸭乙型肝炎病毒（DHBV）复制的影响。B型病毒。一种是红霉素A-9-甲基肟（EMO）和红霉素A的其他肟衍生物，另一种是具有环丁烷环的嘌呤核苷类似物（环丁烷A和环丁烷G）。感染雏鸭肌注EM 0 15 mg/kg，治疗期间血清DHBV DNA水平迅速下降，停药后恢复到治疗前水平。在一些动物中，注射部位存在局部毒性，伴肌肉坏死。当通过胃管给予100 mg/kg EM 0时，未观察到此类病毒应答。对EM 0 15 mg/kg IM和100 mg/kg胃管给药的病毒应答差异不是由于通过不同途径给药未能达到相当的EM 0血液和组织水平。结果表明，IM注射EM 0的间接效应，而不是化合物的直接抗病毒作用，以70 mg/kg IM给药cyclobut G或cyclobut A导致血清中DHBV DNA迅速降低至不可检测的水平，并且仅在4只动物中的1只动物中在停药后10天内再次检测到DHBV DNA。Cyclobut G以180 mg/kg/天的剂量灌胃给药也与所有动物治疗开始时血清DHBV DNA的快速降低相关，在治疗期间5只动物中有4只动物的血清DHBV DNA水平检测不到，并且在停药后所有动物的血清DHBV DNA水平均恢复至治疗前水平。没有明显的毒性作用。在细胞培养中，1 μM cyclobut A或cyclobut G可抑制病毒产生20倍以上，且无明显毒性作用。结果表明，在这些模型中，环丁烯A和环丁烯G在摩尔基础上比其他测试的化合物对DHBV更有活性，并且它们似乎通过口服途径有效。Cyclobut G在细胞培养中抑制HIV-1的活性远低于AZT。
The effects on duck hepatitis B virus (DHBV) replication of specific analogues of two classes of chemical compounds not previously tested against hepadnaviruses are described. One is erythromycin A‐9‐methyloxime (EMO) and other oxime derivatives of erythromycin A, and the other is purine nucleoside analogues (cyclobut A and cyclobut G)with cyclobutane rings. Viral replication was assessed by measuring serum levels of DHBV DNA in infected ducklings and DHBV DNA in infected primary duck hepatocyte cultures.Administration of EM0 15 mg/kg of body weight IM to infected ducklings resulted in a rapid fall in DHBV DNA levels during therapy and a return to pretreatment levels after EM0 administration was stopped. There was local toxicity at injection sites with muscle necrosis in some animals. When 100 mg/kg EM0 was administered by gastric tube no such viral response was observed. The difference in virus response to EM0 15mgikg IM and 100 mgikg by gastric tube was not due to failure to achieve comparable blood and tissue levels of EM0 administered by the different routes. The results suggest an indirect effect dependent on IM injection of EM0 rather than a direct antiviral effect of the compound.Administration of cyclobut G or cyclobut A at 70 mg/kg IM led to a rapid reduction of DHBV DNA to undetectable levels in serum, and in only 1 of 4 animals did DHBV DNA became detectable again within 10 days after stopping the drug. lntragastric administration of cyclobut G at 180 mg/kg per day was also associated with rapid reduction of serum DHBV DNA with onset of treatment in all animals, undetectable levels in 4 of 5 animals during therapy, and return to pretreatment levels in all animals after the drug was stopped. There were no apparent toxic effects. In cell culture 1 μM cyclobut A or cyclobut G inhibited virus production by more than twentyfold without apparent toxic effects. The results indicate that cyclobut A and cyclobut G are more active on a molar basis than other compounds tested against DHBV in these models, and they appear to be effective byu the oral route. Cyclobut G was much less active than AZT in inhibiting HIV‐1 in cell culture.