Three-Dimensional HIV RNA Genome Targeted Drug Leads

描述(由申请人提供)：该项目的总体目标是通过基于三维RNA结构的计算筛选商业上可获得的化合物，利用HIV-1基因组部分的3D结构与选定的RNA靶标结合，开发有前景的药物先导。候选化合物为水溶性、非肽、非核苷酸的小分子有机化合物。这些化合物也应该是很有希望的支架，用于随后的化学修饰，以增强它们的药用性能。该项目需要改进有效靶向RNA的方法。这包括努力使著名的对接计划对靶向RNA更有用。它还需要继续开发一个新的程序，使筛选一个较小的化合物数据库(最多10,000个)，允许诱导与受体匹配。然而，我们非常感兴趣的是，即使在目前的阶段，我们也很有兴趣使用这种方法来发现与重要的HIV RNA结构结合的新的先导化合物，从而可以开发成药物。最有希望的计算“点击”是购买并测试结合到目标RNA通过我们开发的各种分析，包括核磁共振。实验将继续进行，在已经确定的化合物上结合TAR RNA和亲吻环双链，这是在萌芽中的病毒粒子中组装基因组RNA双链所必需的。在待研究的化合物中，有几种已经或正在合成的吩噻嗪类化合物，它们已经或正在合成，以建立与焦油结合的结构-活性关系；吩噻嗪由于毒性低，生物利用度好，是一种很有前途的药物开发支架。将开发一个具有良好生物利用度、低毒性和连接能力的低分子化合物文库，这些化合物已被发现与RNA结合。将使用一种新发现的小分子激动剂来研究亲吻环二聚体向线性二聚体转化的机制，这是组装萌芽病毒粒子所必需的。这种小分子激动剂与核衣壳蛋白NCp7一样可以促进转化。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop promising drug leads via three-dimensional RNA structure based computational screening of commercially available compounds for binding to selected RNA targets utilizing the 3D structure of portions of the HIV-1 genome. Candidates are small water-soluble, nonpeptide, nonnucleotide organic compounds. These compounds should also represent promising scaffolds for subsequent chemical modification to enhance their pharmaceutical properties. The project entails work on improving the methodology for efficient targeting of RNA. This includes working to make the well-known DOCK program more useful for targeting RNA. It also entails continued development of a new program that enables screening of a smaller database of compounds (up to 10,000) permitting induced fit with the receptor. However, we are quite interested in using the methodology even at its current stage to discover new lead compounds that bind to important HIV RNA structures and thus could be developed into drugs. The most promising computational "hits" are purchased and tested for binding to the target RNA via various assays we have developed, including NMR. Experiments will continue on compounds already identified to bind to TAR RNA and to the kissing loop duplex that is essential for assembly of the genomic RNA duplex in the budding virion. Among compounds to be examined are several phenothiazines that have been or are being synthesized to establish a structure-activity relationship for binding to TAR; phenothiazine is a promising scaffold for drug development due to low toxicity and good bioavailability. A library of low molecular weight compounds, with good bioavailability and low toxicity and the capability of being linked, that have been found to bind RNA will be developed. The mechanism of the transformation of the kissing loop dimer to the linear dimer, required for assembly of the budding virion, will be studied using a newly found small molecule agonist that promotes the transformation as does the nucleocapsid protein NCp7.