D,L-ALPHA-DIFLUOROMETHYLORNITHINE INHIBITS HUMAN CYTOMEGALOVIRUS REPLICATION
D,L-ALPHA-DIFLUOROMETHYLORNITHINE INHIBITS HUMAN CYTOMEGALOVIRUS REPLICATION
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DOI：
10.1128/jvi.50.1.145-154.1984
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发表时间：
1984-01-01
影响因子：
5.4
通讯作者：
IRMIERE, A
中科院分区：
文献类型：
--
作者：
GIBSON, W;VANBREEMEN, R;IRMIERE, A
D，L-α-二氟甲基鸟氨酸（DFMO）是鸟氨酸脱羧酶的抑制剂，鸟氨酸脱羧酶是多胺生物合成途径中的第一个酶。暴露人包皮成纤维细胞DFMO感染人株巨细胞病毒（CMV）之前，导致感染性病毒产生的量减少。需要3天的药物暴露才能产生最大的抗病毒作用。在感染时暴露于DFMO的细胞产生正常量的感染性病毒。在感染前1、2或3天预先暴露于该药物，分别导致感染性病毒产生量减少至少10倍、100倍或1000倍。这种减少减少了细胞内亚精胺的损失，并且通过加入外源腐胺、亚精胺或精胺（10 μ M）而部分地避免了。当在感染前3天加入时，DFMO抑制单纯疱疹病毒和猿猴CMV以及人CMV的野生型和实验室原型株的产生。虽然在1 mM的药物浓度下观察到一些抗病毒效果，但10 mM产生更强的效果，并且是常规使用的量。在30 mM DFMO下，未感染细胞的生长减慢但不停止。研究DFMO干扰CMV复制的水平的研究表明，DFMO处理的感染细胞表现出典型的CMV特异性细胞病变效应，合成病毒蛋白和病毒DNA，含有至少一些衣壳形式，并大大减少了脱落到生长培养基中的病毒颗粒的量。由于CMV病毒粒子，像那些单纯疱疹病毒，含有多胺亚精胺和精胺，由于DFMO基本上消除了细胞内亚精胺的池，这种可能性表明，这种药物可能会发挥其抗病毒作用，干扰病毒组装，也许在DNA包装或衣壳蛋白或两者的水平。
D,L-.alpha.-Difluoromethylornithine (DFMO) is an inhibitor of ornithine decarboxylase, the first enzyme in the polyamine biosynthetic pathway. Exposure of human foreskin fibroblast cells to DFMO before their infection with human strains of cytomegalovirus (CMV) resulted in a reduction in the amount of infectious virus produced. A 3-day exposure to the drug was required to elicit maximal antiviral effect. Cells exposed to DFMO at the time of infection produced normal amounts of infectious virus. Preexposure to the drug for 1, 2 or 3 days before infection resulted in at least 10-, 100- or 1000-fold decreases, respectively, in the amount of infectious virus prodcued. This decrease paralleled the loss of intracellular spermidine and was partially spared by the addition of exogenous putrescine, spermidine or spermine (10 .mu.M). When added 3 days before infection, DFMO depressed production of herpes simplex virus and simian CMV, as well as wild-type and laboratory prototype strains of human CMV. Although some antiviral effect was observed at a drug concentration of 1 mM, 10 mM gave a stronger effect and was the amount routinely used. At 30 mM DFMO, growth of noninfected cells was slowed but not arrested. Studies to investigate the level at which DFMO interferes with CMV replication showed tht DFMO-treated, infected cells exhibit a typical CMV-specific cytopathic effect, synthesize both viral proteins and viral DNA, contain at least some capsid forms and shed greatly reduced amounts of virus particles into the growth medium. Since CMV virions, like those of herpes simplex virus, contain the polyamines spermidine and spermine, and since DFMO essentially eliminates the pool of intracellular spermidine, the possibility is suggested that this drug may exert its antiviral effect by interfering with virus assembly, perhaps at the level of DNA packaging or capsid envelopment or both.