Core--Small Molecule Core

核心--小分子核心

• 批准号: 7551251
• 负责人: HARTMUTH C KOLB
• 金额: $ 14.53万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7551251
• 关键词: antiviral agents; biomedical facility; chemical addition; chemical binding; combinatorial chemistry; cyclization; drug discovery /isolation; genetic regulatory element; inhibitor /antagonist; molecular biology information system; virus genetics; virus protein; virus replication

The binding of Rev to a portion of viral RNA, called Rev Response Element (RRE) is a key event in the HIV-1 life cycle, since it regulates the expression of late stage viral proteins and the release of viral RNA into the cytosol. Blocking the Rev-RRE interaction has been shown to inhibit virus replication by preventing these late stage events from taking place. The currently known Rev-RRE inhibitors bind to RNA via ionic interactions (aminoglycosides, arginine derivatives) or by intercalation (heterocycles). The best inhibitors combine both approaches, leading to nanomolar inhibition. However, none of these inhibitors are likely to be developed into drugs, due to bioavailability issues. Hence, there is a great need for cell-permeable small molecular weight compounds that inhibit the Rev-RRE interaction at low concentrations. We plan to investigate whether bioavailable inhibitors of the HIV Rev-RRE interaction can be found using a combinatorial chemistry approach that is based on (a) click chemistry, (b) diversity analysis, (c) computational filtering for drug-likeness, and (d) incorporation of design elements that increase the potential for RNA binding. The specific aims are as follows: 1. Create two in silico libraries of up to 50,000 compounds each based on the most reliable click chemistry reactions. Prioritize compound production based on diversity, drug-likeness and RNA-binding criteria. 2. Produce a library of 2,000 to 2,500 diverse and drug-like compounds based on [3+2] cycloaddition chemistry. 3. Produce a library of 1,500 to 2,000 drug-like compounds that are targeted against RRE. 4. Perform lead optimization with the goal of finding drug-like molecules that are strong inhibitors of Rev-RRE binding in the lower micromolar range.

Rev与一部分病毒RNA的结合称为Rev Response Ements（RRE）是HIV-1生命周期中的关键事件，因为它调节了晚期病毒蛋白的表达以及病毒RNA的释放到细胞质中。阻止Rev-RRE相互作用已显示通过防止这些后期事件发生来抑制病毒复制。当前已知的Rev-RRE抑制剂通过离子相互作用（氨基糖苷，精氨酸衍生物）或通过插入（杂环）结合RNA。最佳抑制剂结合了两种方法，导致纳摩尔抑制作用。但是，由于生物利用度问题，这些抑制剂都不可能发展为药物。因此，非常需要细胞渗透的小分子量化合物，这些化合物抑制了低浓度的Rev-RRE相互作用。我们计划 研究是否可以使用A 基于（a）单击化学的组合化学方法，（b）多样性分析，（c） 用于吸毒的计算过滤，以及（d）掺入设计元素，以增加RNA结合的潜力。具体目的如下：1。根据最可靠的点击化学反应，在多达50,000种化合物的硅库中创建两个。根据多样性，类似毒品和RNA结合标准确定复合生产的优先级。 2。基于[3+2] Cycloadition Chemistry的2,000至2,500种不同的药物样化合物的库。 3。生产一个针对RRE的1,500至2,000种类似药物的化合物的库。 4.执行铅优化，目的是找到在较低的微摩尔范围内的Rev-RRE结合的强抑制剂。