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: 7915001
• 负责人: MARTIN R SCHILLER
• 金额: $ 7.2万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915001
• 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; Libraries; Life Cycle Stages; Lipids; Literature; Maps; Membrane Proteins; Mutagenesis; Mutate; Mutation; NMR Spectroscopy; 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; Screening procedure; 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; recombinant virus; research study; small molecule; src Homology Region 2 Domain; three dimensional structure; tool; trafficking; web site

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 than 15 residues) in protein queries and thus new potential functions in these proteins (http://mnm.engr.uconn.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 (R21, 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; aims 3 and 4.). Validated motifs we be further examined in the R33 component by screening a compound library by Nuclear Magnetic Resonance spectroscopy to identify lead compounds, which will then be tested for inhibition of viral infection and replication (Aims 5 and 6).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.

自身免疫缺陷综合征（AIDS）是由HIV逆转录病毒引起的，IS 全球致命的流行病。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的共识序列 是宿主蛋白的结合位点或靶标的蛋白质作用以允许病毒 感染和复制。例如，HIV信封多蛋白（ENV） 包含一个简短的共识主题（arg-x-lys/arg-arg; x是任何残基） 宿主蛋白酶的裂解，弗林。识别的主要局限性之一 简短的功能主题是缺乏系统的方法和简单的方法 艾滋病毒研究人员的可及性。我们的跨学科团队已建立了Minimotif 矿工（MNM），一个主题数据库和独立于平台的网络工具，可以识别 蛋白质查询中的简短基序共有序列（小于15个残基）和 因此，这些蛋白质的新潜在功能（http://mnm.engr.uconn.edu/）。 这些共识序列中有许多存在于HIV蛋白中。促进 研究艾滋病毒蛋白中短功能基序的研究，我们提出了免费的 新的Web系统基础架构，将蛋白质图案的信息集成到 HIV分离株和HIV蛋白的3D结构之间的序列保守性至 允许HIV研究人员探索HIV蛋白质中的新功能。功能短 图案为干预病毒生命周期提供了许多潜在的靶标 尚未彻底探索的（R21，目标1和2）。第二个目标 该建议是测试一些更令人兴奋的主题预测。共识 HIV蛋白中的基序将通过突变重组中的基序来验证 病毒，测试突变对病毒感染和复制的影响以及 然后分析预测基序的直接函数（例如 另一种蛋白质；目标3和4。）。经过验证的主题，我们在 通过通过核磁筛选复合库来筛选R33组件 共振光谱鉴定铅化合物，然后将测试 为了抑制病毒感染和复制（目标5和6）。该项目提供了一个关键工具，以帮助了解艾滋病毒感染和 在细胞内复制。 提出的实验可能会识别新的铅 用于治疗HIV感染的化合物。