Novel targets for HIV-1: Tat-TAR interactions

HIV-1 的新靶标：Tat-TAR 相互作用

• 批准号: 6405888
• 负责人: Robert Rando
• 金额: $ 14万
• 依托单位: PTC THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-10 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6405888
• 关键词: DNA directed RNA polymerase; antiAIDS agent; antiviral agents; combinatorial chemistry; drug design /synthesis /production; human immunodeficiency virus 1; nucleic acid repetitive sequence; peptide library; protein protein interaction; virus protein; virus replication

DESCRIPTION (Provided by the applicant): The human immunodeficiency virus type-i (HIV-i) is a complex retrovirus that encodes six regulatory proteins, including Tat. The Tat protein is a potent transcriptional activator of the HIV-1 long terminal repeat promoter element. A regulatory element between +1 and +60 in the HIV-1`long terminal repeat which is capable of forming a stable stem-loop structure, designated TAR, is critical for Tat function. In the absence of Tat, RNA polymerase II (pol II) terminates transcription prematurely. Tat-TAR interactions help convert pol II interactions with the RNA template into efficiently produced full-length viral transcripts. We have recently demonstrated that combinatorial libraries composed of tripeptides contained molecules that not only bound to TAR but also inhibited Tat interaction with Tar and subsequent LTR directed transcription was reduced in cell culture. The goal of the proposed research is the discovery of low molecular weight non-peptide compounds that inhibit HIV replication by binding to the TAR RNA element. The success of this research would open the door to new opportunities in the discovery of drugs which bind to discrete RNA structures with possible applications for diseases such as cancer and aids. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE

描述（由申请人提供）：人类免疫缺陷病毒 i 型 (HIV-i) 是一种复杂的逆转录病毒，编码六种调节蛋白， 包括达。 Tat 蛋白是一种有效的转录激活剂 HIV-1长末端重复启动子元件。 +1 之间的监管要素 HIV-1`长末端重复序列中的+60能够形成稳定的 茎环结构（称为 TAR）对于 Tat 功能至关重要。在 缺少 Tat，RNA 聚合酶 II (pol II) 会终止转录 过早地。 Tat-TAR 相互作用有助于转化 pol II 与 RNA 的相互作用 模板转化为有效产生的全长病毒转录本。我们有 最近证明由三肽组成的组合文库 含有不仅与 TAR 结合而且还抑制 Tat 的分子 与 Tar 的相互作用和随后的 LTR 定向转录在 细胞培养。拟议研究的目标是发现低 通过结合抑制 HIV 复制的分子量非肽化合物 到 TAR RNA 元件。这项研究的成功将为新的研究打开大门 发现与离散 RNA 结构结合的药物的机会 可能应用于癌症和艾滋病等疾病。 拟议的商业应用：不可用