Novel targets for HIV-1: Tat-TAR interactions

描述(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， 包括纹身。TAT蛋白是一种有效的转录激活剂 HIV-1长末端重复序列启动子元件。+1之间的监管要素 和HIV-1‘长末端重复序列中的+60，能够形成稳定的 茎环结构，指定为TAR，是TAT功能的关键。在 缺少TAT，RNA聚合酶II(PolII)终止转录 为时过早。TAT-TAR相互作用有助于将PolII与RNA的相互作用转化为 将模板转化为高效生产的全长病毒转录本。我们有 最近证明了由三肽组成的组合文库 包含的分子不仅与焦油结合，而且还抑制TAT 与Tar和随后的LTR定向转录的相互作用在 细胞培养。拟议研究的目标是发现Low 通过结合抑制HIV复制的分子量非肽化合物 到TAR RNA元素。这项研究的成功将为新的 发现与离散RNA结构结合的药物的机会 有可能应用于癌症和艾滋病等疾病。 建议的商业应用：不可用

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