INHIBITION OF THE HIV-1 REV TRANSACTIVATOR

获得性免疫缺陷综合症(AIDS)，一种影响数百万人的疾病 在全世界范围内，患者死亡率都很高。这个 这种疾病的病原体，传染性逆转录病毒-L，已经 事实证明，治疗干预难以奏效。唯一用于治疗的药物 今天的诊所针对的是病毒逆转录酶。充其量这类药物 暂时延缓疾病进展。此外，这些代理人还展示了 在有效治疗剂量下有显著毒性。目前，其他 针对逆转录酶、病毒蛋白酶或病毒的化合物 TAT反式激活剂，ALE也在临床试验中。然而，看起来 明确可能需要针对以下其他步骤的额外药物 病毒复制。其中一个靶点是REV反式激活剂，它是 对病毒复制至关重要。REV的功能是诱导-核 输出部分剪接和未剪接的病毒消息，这些消息编码 传染性HIV-1的结构基因产物和RNA基因组 粒子。我们建议创建一种依赖于REV的双报告分析 结合癌基因科学独特的基于细胞的高通量 筛选技术，能够评估超过12.3万 每年的化合物，以从NCI的天然化合物中识别先导化合物 产品储存库，它特别抑制HIV-1Rev反式- 激活剂。

Acquired Immunodeficiency Syndrome (AIDS), a disease affecting millions of individuals worldwide, has a high incidence of patient mortality. The etiological agent of this disease, the infectious retrovirus HIV-l, has proven refractory to therapeutic intervention. The only drugs used in the clinic today target the viral reverse transcriptase. At best such drugs temporarily delay disease progression. In addition, these agents exhibit significant toxicity at the effective therapeutic dose. Presently, other compounds, targeting reverse transcriptase, viral protease, or the viral Tat trans-activator, ale also in clinical trials. However, it appears clear that additional drugs may be needed which target other steps in viral replication. One such target is the Rev trans-activator, which is essential for viral replication. The function of Rev is to induce-nuclear export of the partially spliced and unspliced viral messages, which encode the structural gene products and the RNA genome, for infectious HIV-1 particles. We propose to create a Rev-dependent, double reporter assay combined with Oncogene Science's unique cell based high-throughput screening technology, which is capable of evaluating over 123,000 compounds per year, to identify lead compounds from the NCI's natural product repository, which specifically inhibit the HIV-1 Rev trans- activator.