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

• 批准号: 7910012
• 负责人: MARTIN R SCHILLER
• 金额: $ 13.05万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7910012
• 关键词: Active Sites; Affect; Amino Acid Motifs; Autoimmune Process; Binding; Binding Sites; Biological Assay; CD4 Lymphocyte Count; Cells; Classification; Collaborations; Collection; Consensus; Consensus Sequence; DNA; Databases; Dimerization; Drug Delivery Systems; Enzymes; Epidemic; Finland; Goals; HIV; HIV Infections; HIV Integrase; HIV Protease; 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

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).

描述（由申请人提供）：自身免疫缺陷综合征（AIDS）是由HIV逆转录病毒引起的，是一种致命的全球流行病。病毒使用的一种有效策略是劫持短功能基序。这些基序是在不同的HIV蛋白上的共有序列，它们是宿主蛋白的结合位点或靶标，可起作用，以允许病毒感染和复制。例如，HIV包络多蛋白（ENV）包含一个短共识基序（arg-x-lys/arg-arg;“ x”是宿主蛋白酶裂解的任何残基）。识别短功能基序的主要局限性之一是缺乏系统的方法和简单的艾滋病毒研究人员可访问性。我们的跨学科团队已建立了MiniMotif Miner（MNM），该矿工（MNM）是一个主题数据库和无独立的网络工具，可在蛋白质查询中识别短序列共识序列（少15个残基），从而在这些蛋白质（http://mmm.ngr.ungr.unconn.edu/）中确定了新的潜在功能。这些共识序列中有许多存在于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Web系统基础架构，该基础结构将蛋白质基序的信息与HIV分离株和HIV蛋白之间的3D结构之间的序列保存相结合，以使HIV研究人员允许HIV研究人员探索HIV蛋白中的新功能。简短的功能基序为尚未彻底探索的病毒生命周期干预提供了许多潜在的靶标（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蛋白中的共识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，然后测定预测基序的直接功能（例如与另一种蛋白质的相互作用； AIM 3）。