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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

基本信息

批准号：
7268036
负责人：
Ramachandra S Hosmane
金额：
$ 23.69万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE COUNTY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7268036
关键词：
Address Affect Antiviral Agents Applications Grants Biological Biological Assay California Carbon Cells Collaborations Communicable Diseases Data Depth Diphosphates Drug Exposure Event Gene Expression Genetic Transcription Goals HIV HIV-1 Health Hepatitis C virus Human Cloning Immunology In Vitro Individual Infection Inhibitory Concentration 50 Integration Host Factors International Investigation Laboratories Lactamase Lead Length Letters Life Cycle Stages Location Mails Medicine Methods Microbiology Molecular Molecular Genetics Molecular Virology Mono-S Mutation National Institute of Allergy and Infectious Disease Nuclear Nuclear Export Nucleic Acids Nucleosides Pharmaceutical Preparations Phase Phosphorylation Polymerase Chain Reaction Positioning Attribute Production Proviruses Public Health Schools RNA Range Regulation Research Research Personnel Research Project Grants Resistance Reverse Transcription Ribose Role Sampling Scientist Staging Standards of Weights and Measures Structure-Activity Relationship Techniques Time Toxic effect Universities Viral Viral Genome Viral Physiology Virus Virus Replication Work analog anti-hepatitis C antiviral nucleoside analog aptamer base college in vivo mutant novel nucleoside analog particle professor programs skills sugar tripolyphosphate vector

项目摘要

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(申请人提供)：我们最近发现了一种新的扩环核苷(REN)，它在体外有效地抑制人类免疫缺陷病毒(HIV)和丙型肝炎病毒(HCV)，对这两种病毒的IC50值分别在微摩尔和纳摩尔范围内，对宿主细胞几乎没有毒性。由于丙型肝炎病毒是HIV感染者的一种主要混合感染，因此发现一种能够双重抑制艾滋病毒和丙型肝炎病毒的化合物，这两种可怕的病毒引起了当前国家和国际健康问题的关注，具有重要的生物医学意义，值得进一步探索。这项建议特别侧重于研究该化合物的抗HIV活性的机制。由于在这方面一无所知，我们打算使用这个R21应用程序来快速获取一些关于受REN影响的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，以深入研究针对病毒生命周期阶段的抗艾滋病毒活性的机制，并反过来为广泛的SAR研究奠定基础。这里要解决的重要问题包括：(A)REN是否对病毒的产生或病毒抑制发挥作用，(B)它是否抑制病毒生命周期中的早期事件，包括病毒进入、反转录、核定位和整合，或后来的事件，包括整合的前病毒的转录、核输出、组装和颗粒产生，(C)考虑到许多核苷类似物的活性形式已知是其相应的一、二或三磷酸衍生物，以及(D)考虑到许多抗病毒核苷类似物都是通过这种机制工作的，REN的活性机制是否涉及通过它们的5‘-三磷酸衍生物进入核酸并随后链终止。此外，我们将合成几个精选的先导化合物类似物，看看是否可以进一步增强抗病毒活性。这包括(A)合成铅Ren的核糖类似物，以及(B)将-6位的烷基链再延伸几个碳原子。最后，我们将调查领先的REN及其类似物是否对耐药的HIV突变体有效。