Identification of short functional motifs as potential drug targets for HIV

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。这些基序是不同HIV蛋白上的共识序列，它们是宿主蛋白作用的结合位点或靶标，从而允许病毒感染和复制。例如，HIV包膜多蛋白（Env）包含一个短的共识基序（Arg-x-Lys/Arg-Arg；“x”是任何残基），可被宿主蛋白酶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。我们的跨学科团队已经建立了Minimotif Miner (MnM)，这是一个motif数据库和平台无关的网络工具，可以识别蛋白质查询中的短motif共识序列（少于15个残基），从而确定这些蛋白质的新潜在功能（http://mmm.engr.unconn.edu/）。许多这些共识序列存在于HIV蛋白中。为了促进对HIV蛋白中短功能基序的研究，我们提出提供一个免费的新的web系统基础设施，该系统集成了HIV分离物中蛋白质基序的序列守恒信息和HIV蛋白的3D结构，使HIV研究人员能够探索HIV蛋白中的新功能。短功能基序为干预病毒生命周期提供了大量尚未被彻底探索的潜在靶标（目的1和2）。这个提议的第二个目标是测试一些更令人兴奋的母题预测。HIV蛋白中的共识基序将通过在重组病毒中突变基序来验证，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）。公共卫生相关性：该项目提供了一个关键工具，有助于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治疗HIV感染的新先导化合物。

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.