HIV FRAMESHIFTING--FROM BIOLOGY TO THERAPEUTICS

HIV框架转移——从生物学到治疗学

• 批准号: 6497114
• 负责人: STUART W PELTZ
• 金额: $ 25.26万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497114
• 关键词: antiAIDS agent; antiviral agents; drug design /synthesis /production; frameshift mutation; genetic translation; human immunodeficiency virus 1; nucleic acid sequence; ribosomes; tissue /cell culture; virus RNA; virus genetics; virus replication

DESCRIPTION (Adapted from applicant's abstract): The ability of ribosomes to maintain the correct translational reading frame is fundamental to the integrity of protein synthesis and to cell growth and viability. However, there are now a number of examples utilized by viruses in which elongating ribosomes are programmed to shift their translational reading frame one base in the 5' direction. This process is called programmed -1 ribosomal frame-shifting. Programmed -1 ribosomal frame-shifting is utilized uniquely by eucaryotic viruses, making it a compelling target for developing antiviral agents. The human immunodeficiency virus type 1 (HIV-1) utilizes a programmed -1 ribosomal frameshift to synthesize both the gag and gag-pol proteins from a single transcript. They have been investigating the cis-acting elements and trans-acting factors that determine programmed -1 ribosomal frame-shifting efficiencies in the yeast Saccharomyces cerevisiae. Using the double-stranded L-A virus system, they have shown that small changes in the ratio of the gag to gag-pol synthesized by altering frame-shifting efficiency leads to a loss of the killer virus. These findings have led them to develop the concept that antiviral agents can be identified that alter the efficiency of programmed frame-shifting without dramatically affecting global protein synthesis. They have successfully demonstrated this principle using the yeast killer virus system as the model, and more recently, with HIV in mammalian cells. Based on these investigations, they propose to characterize programmed -1 frame-shifting in HIV-1 with the goal of developing this virus specific mechanism as a target for antiviral intervention. The aims of the experiments proposed in this grant proposal will be to characterize the sequences that promote efficient frame-shifting in HIV-1 and to determine the affects of altering frame-shifting efficiency on HIV production. They will also characterize further determine if putative compounds that alter programmed -1 frame-shifting and promote loss of the killer virus will also reduce or eliminate HIV production. Additional compounds that affect programmed frame-shifting will also be identified. Finally, they will investigate at the molecular level how compounds that affect programmed frame-shifting function. Their long-term goal will be to develop compounds that affect frame-shifting to the point that proof of principle has been established and antiviral agents targeting this process will be subsequently developed for clinical use.

描述（改编自申请人摘要）：核糖体的能力， 保持正确的翻译阅读框架是基本的 蛋白质合成的完整性以及细胞生长和活力。但 现在是病毒利用的一些例子，其中延长核糖体 将它们的翻译阅读框在5'端移动一个碱基 方向这个过程被称为程序性核糖体移码。 真核生物独特地利用程序化-1核糖体移码 病毒，使其成为开发抗病毒剂的一个引人注目的目标。的 人类免疫缺陷病毒1型（HIV-1）利用程序化的-1核糖体 移码以从单一的细胞合成gag和gag-pol蛋白质 成绩单。他们一直在研究顺式作用元件， 决定程序性核糖体移码的反式作用因子 在酵母Saccharomyces cerevisiae中的效率。使用双链 L-A病毒系统，他们已经表明，在gag与 通过改变移帧效率合成的gag-pol导致 杀手病毒。这些发现使他们发展出一个概念， 可以鉴定出改变程序化的抗病毒药物的效率的抗病毒剂， 移码而不显著影响整体蛋白质合成。他们 已经成功地用酵母杀手病毒证明了这一原理 系统作为模型，最近，在哺乳动物细胞中使用HIV。基于 这些研究中，他们建议描述程序化移帧 目的是开发这种病毒特异性机制作为靶点 进行抗病毒干预。这项拨款中提出的实验目的 建议将是表征序列，促进有效的 HIV-1的移码，并确定改变移码的影响 生产艾滋病毒的效率。他们还将进一步确定是否 假定的化合物改变程序性移码并促进 这种致命病毒还将减少或消除艾滋病毒的产生。额外 还将鉴定影响程序性移码的化合物。 最后，他们将在分子水平上研究化合物如何影响 可编程移帧功能。他们的长期目标是发展 这些化合物会影响框架转换， 已经建立，针对这一过程的抗病毒药将被 随后开发用于临床。