HIV FRAMESHIFTING--FROM BIOLOGY TO THERAPEUTICS

HIV框架转移——从生物学到治疗学

• 批准号: 6020023
• 负责人: STUART W PELTZ
• 金额: $ 12.34万
• 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/6020023
• 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（改编自申请人的摘要）：核糖体的能力 保持正确的翻译阅读框架是 蛋白质合成以及细胞生长和活力的完整性。但是，那里 现在是通过伸长核糖体的病毒使用的许多例子 被编程以在5'中移动他们的翻译阅读框架。 方向。此过程称为编程-1核糖体框架移动。 编程-1核糖体框架移动由桉树唯一利用 病毒，使其成为开发抗病毒剂的引人注目的目标。这 人类免疫缺陷病毒1型（HIV -1）使用了编程的-1核糖体 从单个的移料机合成插科打蛋白和GAG-POL蛋白 成绩单。他们一直在研究顺式作用元素， 决定编程的-1核糖体框架移动的跨作用因子 酿酒酵母的酵母糖疗法的效率。使用双链 L-A病毒系统，他们已经表明，GAG与 通过改变框架转移效率而合成的GAG-POL会导致损失 杀手病毒。这些发现使他们发展了一个概念 可以确定抗病毒剂，以改变编程的效率 框架移动而不会显着影响全局蛋白质合成。他们 使用酵母菌病毒成功证明了这一原理 系统作为模型，以及最近的哺乳动物细胞中的HIV。基于 这些调查，他们建议表征编程的-1帧移动 在HIV-1中，目的是开发该病毒特定机制作为目标 用于抗病毒干预。这笔赠款提出的实验的目的 建议将表征促进有效效率的序列 HIV-1中的框架移动并确定改变框架移动的影响 艾滋病毒产生的效率。他们还将进一步确定是否是否 推定的化合物可以改变编程的-1帧移动并促进损失 杀手病毒还将减少或消除艾滋病毒的产生。额外的 还将确定影响编程帧移动的化合物。 最后，他们将在分子水平上调查如何影响化合物 编程帧移动功能。他们的长期目标是发展 影响框架转移到原则证明的地步的化合物 已建立，针对此过程的抗病毒剂将是 随后开发用于临床用途。