GENOME TARGETED INHIBITORS OF RETROVIRUSES

基因组靶向逆转录病毒抑制剂

• 批准号: 6170761
• 负责人: Virendra Nath PANDEY
• 金额: $ 22.44万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6170761
• 关键词: Retroviridae; antiAIDS agent; antisense nucleic acid; antiviral agents; binding sites; cytotoxicity; drug delivery systems; drug screening /evaluation; gel mobility shift assay; gene expression; genetic regulation; genetic transduction; human immunodeficiency virus 1; intermolecular interaction; nucleic acid inhibitor; nucleic acid repetitive sequence; nucleic acid sequence; tissue /cell culture; transcription factor; virus DNA; virus RNA; virus genetics

DESCRIPTION: (Adapted from Applicant's Abstract) The major thrust of this application continues to aim at targeting invariant non-translated domains at the 5'-end of the HIV genome with specifically designed polyamide nucleic acids (PNAs) and their derivatives. The ability of these genome specific antisense inhibitors to block various steps of viral replication will be assessed in order to develop effective multiprong drugs of high therapeutic index. The proposal has five specific aims: Aim 1- To target the primer binding site (PBS) region A- loop region and the stem-loop bulge structure of the viral genome, block their interaction with tRNA3Lys and thus inhibit reverse transcription; Aim 2 - To target the repeat region (R) of the LTR and the att site on the 5' and 3' LTR of the HIV genome to prevent the strand transfer reaction and integration of the proviral genome; Aim 3 - To target the TAR region of the viral RNA genome to prevent its interaction with regulatory transactivating Tat protein; Aim 4 - To develop an effective biodelivery system for promising antisense PNAs; and Aim 5 - To evaluate the in vitro anti viral efficacy and cytotoxicity of the lead PNA compounds in MT-2 cell cultures infected with HIV-1.

描述：（改编自申请人的摘要） 该应用程序继续旨在针对不变的非翻译 艾滋病毒基因组5'末端的域，特定设计 聚酰胺核酸（PNA）及其衍生物。能力 这些基因组特异性反义抑制剂，以阻止 将评估病毒复制以发展有效 高治疗指数的多方面药物。该提议有五个 具体目的：目标1-靶向底漆结合位点（PBS）区域A- 循环区域和病毒基因组的茎环凸起结构 它们与tRNA3lys的相互作用，从而抑制逆转录； 目标2-针对LTR的重复区域（R）和ATT位点的重复区域（R） HIV基因组的5'和3'LTR，以防止链转移 病毒基因组的反应和整合；目标3-针对 病毒RNA基因组的焦油区域，以防止其与 调节反式激活TAT蛋白；目标4-发展有效 有望反义PNA的生物传递系统；目标5-评估 铅PNA的体外抗病毒疗效和细胞毒性 感染HIV-1的MT-2细胞培养物中的化合物。