Bis-anthracycline antibiotics inhibit human immunodeficiency virus type 1 transcription
Bis-anthracycline antibiotics inhibit human immunodeficiency virus type 1 transcription
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DOI：
10.1128/aac.48.5.1652-1663.2004
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发表时间：
2004-05-01
影响因子：
4.9
通讯作者：
Benveniste, EN
中科院分区：
文献类型：
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作者：
Kutsch, O;Levy, DN;Benveniste, EN
人类免疫缺陷病毒1型(HIV-1)毒株对目前使用的抗逆转录病毒药物具有耐药性，这就要求开发新的有效的抗逆转录病毒化合物。TAT反式激活很早就被认为是药物干扰的一个有吸引力的靶点。为了筛选和分析干扰TAT反式激活的化合物的影响，我们开发了几种基于细胞的报告系统，其中增强的绿色荧光蛋白是HIV-1表达或TAT依赖的长末端重复序列活性的直接和定量标记物。利用这些报告细胞系，我们发现最近开发的DNA嵌入剂双-蒽环类药物WP631在亚细胞毒性浓度下有效地抑制了HIV-1的表达。WP631还消除了感染各种初级病毒分离株的外周血单个核细胞中的HIV-1急性复制。我们证明WP631介导的HIV-1抑制是通过抑制TAT反式激活而引起的。这些数据表明，WP631可以作为一种新型HIV-1抑制剂的先导化合物。
The increasing numbers of human immunodeficiency virus type 1 (HIV-1) strains that exhibit resistance to antiretroviral agents used at present require the development of new effective antiretroviral compounds. Tat transactivation was recognized early on as an attractive target for drug interference. To screen for and analyze the effects of compounds that interfere with Tat transactivation, we developed several cell-based reporter systems in which enhanced green fluorescence protein is a direct and quantitative marker of HIV-1 expression or Tat-dependent long terminal repeat activity. Using these reporter cell lines, we found that the bis-anthracycline WP631, a recently developed DNA intercalator, efficiently inhibits HIV-1 expression at subcytotoxic concentrations. WP631 also abrogated acute HIV-1 replication in peripheral blood mononuclear cells infected with various primary virus isolates. We demonstrate that WP631-mediated HIV-1 inhibition is caused by the inhibition of Tat transactivation. The data presented suggest that WP631 could serve as a lead compound for a new type of HIV-1 inhibitor.