VIF anatagonist: lead Inhibitor Identification

根据世界卫生组织的数据，2003年有480万人新感染艾滋病毒 使艾滋病毒携带者总数达到约3780万人。从第一个艾滋病病例开始 自1981年被发现以来，已有超过2000万人死于这种疾病。尽管医学上取得了显著的进步， HIV-1感染继续增加。我们的目标是针对一个新的和未开发的目标来识别药物 用于治疗艾滋病。人类免疫缺陷病毒1型(HIV-1)，艾滋病的病原体， 是一种复杂的逆转录病毒，编码六种调节蛋白，包括对病毒复制至关重要的Vif 在活体内。由于目前还没有已知的HIV-1Vif的细胞同源物，这种蛋白代表着一种极端的 抗病毒干预的目标很有吸引力，但尚未实现。因此，我们建议确定铅抑制物 HIV-1 Vif功能。我们的具体目标如下：(1)Vif抑制剂的鉴定。实验是 建议开发高度可靠和可重复性的基于荧光的分析方法来监测HIV-1 Vif 在蜂窝环境中发挥作用。将使用高通量筛查分析来识别小分子 可以靶向Vif-APOBEC3G相互作用的分子抑制剂。(2)结构活性关系研究和 先导化合物的验证。建议进行实验以表征该病毒的有效性和特异性。 从初步筛选实验中确定为Vif抑制剂的化合物。选定的化合物将进行测试 在许可和非许可牢房中的抗艾滋病毒Vif活动(项目2)。丹参的抗病毒活性 将对选定的针对HIV-1临床分离株的Vif拮抗剂进行分析，并对安全性和稳定性进行描述 将确定这些化合物的含量(核心B)。VIF拮抗剂活动在慢性心力衰竭中的后果 受感染的猕猴将在项目3中进行调查。作为对药理学研究的支持(项目3和 核心B)，我们将测量药物处理动物的血浆中的药物浓度。根据活动情况， 稳定性和毒性数据(项目2和3，以及核心B)，将合成新化合物以改善 铅结构的有效性和选择性。(3)Vif抑制机制(S)。我们将进行一些实验 从分子水平了解Vif抑制剂的作用机制。

According to the World Health Organization, 4.8 million people were newly infected with HIV in 2003 bringing the total number to some 37.8 million people who are living with HIV. Since the first cases of AIDS were identified in 1981, over 20 million have died by this disease. In spite of remarkable medical advances, HIV-1 infections continue to increase. Our goal is to identify drugs against a novel and unexploited target for the treatment of AIDS. The human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS, is a complex retrovirus that encodes six regulatory proteins, including Vif that is essential for viral replication in vivo. Since there are no known cellular homologs of HIV-1 Vif, this protein represents an extremely attractive, yet unrealized, target for antiviral intervention. Therefore, we propose to identify lead inhibitors of HIV-1 Vif function. Our specific aims are as follows: (1) Identification of Vif inhibitors. Experiments are proposed to develop highly robust and reproducible fluorescence-based assays to monitor HIV-1 Vif function in cellular environment. High throughput screening assays will be employed to identify small molecule inhibitors that can target Vif-APOBEC3G interactions. (2) Structure activity relation studies and validation of lead compounds. Experiments are proposed to characterize the efficacy and specificity of the compounds identified as Vif inhibitors from initial screening experiments. Selected compounds will be tested for their anti-HIV Vif activities in both permissive and non-permissive cells (Project #2). Antiviral activities of selected Vif antagonists against clinical HIV-1 isolates will be analyzed and the safety and stability profiles of these compounds will be determined (core B). Consequences of Vif antagonist's activities in chronically infected macaques will be investigated in project #3. As a support to pharmacology studies (project #3 and core B), we will measure the drug concentrations in plasma of drug treated animals. Based on the activity, stability, and toxicity data (projects 2 and 3, and core B), new compounds will be synthesized to improve the potency and selectivity of lead structures. (3) Mechanism(s) of Vif inhibition. Experiments will be performed to understand the mechanism of Vif inhibitors at molecular level.