Identification of short functional motifs as potential drug targets for HIV

鉴定短功能基序作为 HIV 潜在药物靶标

基本信息

批准号：
7632276
负责人：
MARTIN R SCHILLER
金额：
$ 1.75万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-15 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7632276
关键词：
Active Sites Affect Amino Acid Motifs Autoimmune Process Binding Binding Sites Biological Assay CD4 Lymphocyte Count Cells Classification Co-Immunoprecipitations Collaborations Collection Consensus Consensus Sequence DNA Databases Dimerization Drug Delivery Systems Enzymes Epidemic Finland Goals HIV HIV Infections HIV Integrase HIV Protease HIV-1 ITIM Internet Intervention Lead Letters Life Cycle Stages Lipids Literature Maps Membrane Proteins Mutagenesis Mutate Mutation Nucleic Acids Peptide Hydrolases Pharmaceutical Preparations Plasma Post-Translational Protein Processing Process Protein Binding Proteins RNA-Directed DNA Polymerase Research Infrastructure Research Personnel Resistance Retroviridae Structure Surface Symptoms Syndrome System Testing Treatment Protocols Universities Viral Viral Genome Virus Virus Diseases arginylarginine clinically significant env Gene Products follow-up new therapeutic target platform-independent protein structure public health relevance recombinant virus research study small molecule src Homology Region 2 Domain three dimensional structure tool trafficking web site

项目摘要

DESCRIPTION (provided by applicant): Autoimmune Deficiency Syndrome (AIDS) is caused by the HIV retrovirus and is a deadly worldwide epidemic. One efficient strategy that viruses use is to hijack short functional motifs. These motifs are consensus sequences on different HIV proteins that are the binding sites or targets that host proteins act on to allow viral infection and replication. For example, the HIV envelope polyprotein (Env) contains a short consensus motif (Arg-x-Lys/Arg-Arg; "x" is any residue) for cleavage by the host protease, Furin. One of the major limitations in identifying short functional motifs is the lack of a systematic approach and simple accessibility for HIV researchers. Our cross-disciplinary team has built Minimotif Miner (MnM), a motif database and platform-independent web-tool that identifies short motif consensus sequences (less that 15 residues) in protein queries and thus new potential functions in these proteins (http://mmm.engr.unconn.edu/). Many of these consensus sequences are present in HIV proteins. To facilitate the study of short functional motifs in HIV proteins, we proposed to provide a free new web system infrastructure that integrates information for protein motifs with sequence conservation among HIV isolates and 3D structures of HIV proteins to allow HIV researchers to explore new functions in HIV proteins. Short functional motifs provide a plethora of potential targets for intervention in the viral life-cycle that have not been thoroughly explored (Aims 1 and 2). A second goal of this proposal is to test some of the more exciting motif predictions. Consensus motifs in HIV proteins will be validated by mutating the motif in recombinant viruses, testing for the effect of the mutation on viral infection and replication, and then assaying the direct function of the predicted motif (e.g. interaction with another protein; aim 3). PUBLIC HEALTH RELEVANCE: This project provides a key tool to help understand the process by which HIV infects and replicates within cells. The proposed experiments are likely to identify new lead compounds for treating HIV infection.

描述（由申请人提供）：自身免疫缺陷综合症（艾滋病）是由艾滋病毒逆转录病毒引起的，是一种致命的世界性流行病。病毒使用的一种有效策略是劫持短功能基序。这些基序是不同 HIV 蛋白上的共有序列，这些蛋白是宿主蛋白作用以允许病毒感染和复制的结合位点或靶标。例如，HIV 包膜多蛋白 (Env) 包含一个短的共有基序（Arg-x-Lys/Arg-Arg；“x”是任何残基），用于被宿主蛋白酶 Furin 切割。识别短功能基序的主要限制之一是缺乏系统的方法和艾滋病毒研究人员的简单可及性。我们的跨学科团队构建了 Minimotif Miner (MnM)，这是一个基序数据库和独立于平台的网络工具，可识别蛋白质查询中的短基序共有序列（少于 15 个残基），从而识别这些蛋白质中的新潜在功能 (http:// /mmm.engr.unconn.edu/)。许多共有序列存在于 HIV 蛋白中。为了促进 HIV 蛋白中短功能基序的研究，我们建议提供一个免费的新网络系统基础设施，该基础设施将蛋白质基序的信息与 HIV 分离株之间的序列保守性和 HIV 蛋白的 3D 结构集成在一起，使 HIV 研究人员能够探索 HIV 中的新功能蛋白质。短功能基序为干预病毒生命周期提供了大量尚未彻底探索的潜在目标（目标 1 和 2）。该提案的第二个目标是测试一些更令人兴奋的主题预测。 HIV 蛋白中的共有基序将通过突变重组病毒中的基序、测试突变对病毒感染和复制的影响、然后分析预测基序的直接功能（例如与另一种蛋白质的相互作用；目标 3）来验证。公共健康相关性：该项目提供了一个关键工具，帮助了解艾滋病毒在细胞内感染和复制的过程。拟议的实验可能会发现用于治疗艾滋病毒感染的新先导化合物。