INHIBITION OF HIV GENE TRANSCRIPTION BY SMALL MOLECULES

小分子抑制 HIV 基因转录

• 批准号: 6700741
• 负责人: JOEL M. GOTTESFELD
• 金额: $ 50.44万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6700741
• 关键词: DNA footprinting; SCID mouse; adult human (21+); amides; antiAIDS agent; antiviral agents; binding sites; cell line; chemical synthesis; combinatorial chemistry; drug design /synthesis /production; enzyme inhibitors; genetic regulatory element; genetic transcription; human immunodeficiency virus; human tissue; imidazole; microarray technology; nonhuman therapy evaluation; pharmacokinetics; polymers; protein protein interaction; pyrroles; transcription factor; virus replication

DESCRIPTION: This is a continuation application for a program aimed at development of new drugs for the treatment of human acquired immunodeficiency syndrome by interference with HIV-1 RNA transcription. Our studies have focused on the pyrrole-imidazole polyamides, developed in the laboratory of the Co-PI, Dr. Peter Dervan at Caltech. These molecules can be designed and synthesized to target a wide range of DNA sequences with subnanomolar affinities, comparable to the affinities of cellular transcription factors for their DNA targets. During the previous years of support, we have developed polyamide ligands to target the binding sites for the host cell regulatory proteins involved in HIV-l RNA transcription. Studies in the laboratory of Dr. J. Gottesfeld at the Scripps Research Institute have shown that these molecules inhibit specific transcription factor-DNA interactions on the HIV-1 promoter and enhancer and are potent inhibitors of HIV-1 transcription in vitro. Importantly, through a collaborative effort with Dr. D. Mosier at Scripps, we have shown that these polyamides are effective inhibitors of HIV-1 replication in human peripheral blood lymphocytes. We now propose to optimize our DNA targets within the HIV-1 enhancer and promoter elements and to validate the hypothesis that inhibition of virus replication is a direct consequence of inhibition of protein-DNA interactions on the integrated HIV-1 proviral DNA. We will determine whether polyamides can access their target sequences in the context of cellular chromatin and we will examine the genome-wide effects of polyamide treatment using DNA array technology. Given our success in inhibition of virus replication in cell culture, we propose collaborative preclinical studies with the Mosier laboratory to determine the effectiveness of polyamides in the human PBL-SCID mouse model.

描述：这是针对计划的程序的延续应用 开发用于治疗人类获得的免疫缺陷的新药 综合征通过干扰HIV-1 RNA转录。我们的研究集中 在co-pi实验室中开发的吡咯 - 咪唑在聚酰胺上， 加州理工学院的Peter Dervan博士。这些分子可以设计和合成至 靶向具有亚洋摩尔亲和力的广泛的DNA序列，可比 对于其DNA靶标的细胞转录因子的亲和力。 在支持的前几年，我们开发了聚酰胺配体 针对涉及宿主细胞调节蛋白的结合位点 HIV-L RNA转录。 J. Gottesfeld博士的研究 Scripps研究所表明，这些分子抑制了特异性 HIV-1启动子和增强子上的转录因子-DNA相互作用以及 是在体外的HIV-1转录的有效抑制剂。重要的是，通过一个 与Scripps的D. Mosier博士的合作努力，我们已经证明了这些 聚酰胺是人外周中HIV-1复制的有效抑制剂 血液淋巴细胞。我们现在建议在HIV-1中优化我们的DNA靶标 增强子和启动子元素，并验证抑制作用的假设 病毒复制是抑制蛋白-DNA的直接结果 在综合HIV-1前病毒DNA上的相互作用。我们将确定是否 聚酰胺可以在细胞中访问其目标序列 染色质，我们将检查多酰胺治疗的全基因组效应 使用DNA阵列技术。考虑到我们在抑制病毒方面的成功 在细胞培养中的复制，我们提出了与 Mosier实验室确定聚酰胺在人类中的有效性 PBL-SCID鼠标模型。