ANTI-REVERSE TRANSCRIPTASE ACTIVITY OF GLIOTOXIN ANALOGS
ANTI-REVERSE TRANSCRIPTASE ACTIVITY OF GLIOTOXIN ANALOGS
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DOI：
10.1016/0006-2952(78)90497-5
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发表时间：
1978-01-01
影响因子：
5.8
通讯作者：
HERSCHEID, JDM
中科院分区：
文献类型：
--
作者：
DECLERCQ, E;BILLIAU, A;HERSCHEID, JDM
在表硫二氧基哌嗪部分含有1、2、3或4个硫原子的Gliotoxs类似物，被发现能抑制RNA肿瘤病毒[小鼠(Moloney)白血病病毒]相关的RNA诱导的POA聚合酶(逆转录酶)活性，并能抑制小鼠(Moloney)肉瘤病毒对正常小鼠(MO)细胞的转化。胶质毒素类似物的抗逆转录酶活性依赖于表硫二氧基哌嗪环上的硫原子数，因为四硫化物和三硫化物比二硫化物具有更强的抑制作用，而二硫化物又比一硫化物具有更强的抑制作用。胶质毒素类似物对逆转录酶反应的抑制不能归因于对必需的辅因子Mn2+或Zn2+的螯合作用，因为胶质毒素类似物在高于最佳浓度的Mn2+和Zn2+浓度下仍保持其抑制作用。然而，在大量的还原剂如二硫苏糖醇的存在下，胶质毒素类似物抑制逆转录酶反应的能力被取消。因此，似乎胶质毒素类似物的抗逆转录酶活性直接依赖于表硫代二氧基哌嗪环上完整的二硫、三硫或四硫键。
Gliotoxin analogs, containing 1, 2, 3 or 4 sulfur atoms in their epithiodioxopiperazine moiety, were found to inhibit the RNA-directed poA polymerase (reverse transcriptase) activity associated with RNA tumor viruses [murine (Moloney) leukemia virus] and to suppress the transformation of normal mouse (MO) cells by murine (Moloney) sarcoma virus. The antireverse transcriptase activity of the gliotoxin analogs depended on the number of sulfur atoms in the epithiodioxopiperazine ring in as far as the tetra- and trisulfides proved more inhibitory than the disulfide which, in turn, proved more inhibitory than the monosulfide. Inhibition of the reverse transcriptase reaction by the gliotoxin analogs could not be attributed to chelation of Mn2+or Zn2+, the necessary cofactors, since the gliotoxin analogs retained their inhibitory effects at supra-optimal Mn2+and Zn2+concentrations. However, the ability of the gliotoxin analogs to inhibit the reverse transcriptase reaction was abolished in the presence of a large excess of reducing agensts such as dithiothreitol. It would appear, therefore, that the antireverse transcriptase activity of the gliotoxin analogs directly depends on an intact di-,tri or tetra-sulfide bridge in the epithiodioxopiperazine ring.