Mechanistic Studies of Anti-HIV Activity of a Novel Ring-Expanded Nucleoside

新型扩环核苷抗HIV活性的机制研究

• 批准号: 7274009
• 负责人: Ramachandra S Hosmane
• 金额: $ 4.85万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7274009
• 关键词: Mechanistic; Studies; Anti; HIV; Activity

DESCRIPTION (provided by applicant): We have recently discovered a novel ring-expanded nucleoside (REN) that potently inhibits both the human immunodeficiency virus (HIV) as well as the hepatitis C virus (HCV) in vitro with IC50 values in the micromolar and nanomolar ranges, respectively, for the two viruses, with little toxicity, if any, to the host cells. Since HCV is a major co-infection in the HIV-infected individuals, the discovery of a compound capable of dual viral inhibition of HIV and HCV, the two dreaded viruses eliciting current national and international health concern, is biomedically significant and merits further exploration. This proposal specifically focuses on investigation of the mechanism of anti-HIV activity of the compound. Since nothing is known on this front, we intend to use this R21 application to quickly acquire some important preliminary data concerning the stage of the viral life cycle that is being affected by the REN. These preliminary data would serve as the basis for a subsequent R01 application for an in-depth investigation of the mechanism of anti-HIV activity specific to the stage of the viral life cycle, and in turn, for the extensive SAR studies. The important questions to be addressed in here include: (a) whether the REN exerts its effect on the virus production or virus inhibition, (b) whether it inhibits the early events in the viral life cycle, including the viral entry, reverse transcription, nuclear localization and integration, or later events, including transcription of the integrated provirus, nuclear export, assembly and particle production, (c) whether in vivo phosphorylation of the REN is necessary for it to be active, considering that the active forms of many, if not all, nucleoside analogues are known to be their corresponding mono-, di-, or triphosphate derivatives, and (d) whether the mechanism of activity of REN involves incorporation into nucleic acids via their 5'-triphosphate derivatives and subsequent chain termination, considering that many antiviral nucleoside analogues are known to operate by this mechanism. In addition, we will synthesize a few selected analogues of the lead compound to see if the antiviral activity could be further enhanced. This includes (a) synthesis of the ribose analogue of the lead REN, and (b) extending the alkyl chain at position-6 by a few more carbon atoms. Finally, we will investigate if the leading REN as well as its analogues are effective against the resistant HIV mutants.

描述（由申请人提供）：我们最近发现了一种新型的环环核苷（REN），可有效抑制人类免疫缺陷病毒（HIV）以及丙型肝炎病毒（HCV）在体外具有IC50值，而在微极和纳米极范围内，有两种病毒的细胞，如果有任何毒性，则分别具有造成物质的细胞，如果有任何毒性，如果有任何毒性，如果有任何毒性，对于任何毒性而言，造型均可构成造型。由于HCV是艾滋病毒感染者的主要共同感染，因此发现了能够双重病毒抑制艾滋病毒和HCV的化合物，因此引起当前国家和国际健康关注的两个可怕的病毒在生物医学上具有重要意义，因此具有进一步的探索。该提案特别着重于研究该化合物抗HIV活性机制。由于在这方面尚未知道，因此我们打算使用此R21应用程序快速获取有关REN影响的有关病毒生命周期阶段的重要初步数据。这些初步数据将作为随后的R01申请的基础，以深入研究病毒生命周期阶段的抗HIV活性机理，而反过来又进行了广泛的SAR研究。此处要解决的重要问题包括：（a）REN是否对病毒产生或抑制病毒抑制作用，（b）它是否抑制病毒生命周期中的早期事件，包括病毒式进入，逆转录，核定位，核定位和整合，还是以后的事件，还是以前的核心，核心的生产，包括核心，核出口和粒子的转录，（c）主动，考虑到许多（如果不是全部）的活性形式，核苷类似物被称为相应的单，二磷酸或三磷酸衍生物，以及（d）REN的活性机制是否涉及通过其5'-三磷酸盐衍生物纳入核酸的核酸纳入核酸，并以这种抗核酸的态度为单位，这些机制是对这些抗生素的机制。此外，我们将合成一些铅化合物的一些选定类似物，以查看是否可以进一步增强抗病毒活性。这包括（a）铅ren的核糖类似物的合成，以及（b）在位置6处将烷基链扩展到其他几个碳原子。最后，我们将研究领先的REN及其类似物是否有效抵抗抗性HIV突变体。