Specific activation of latent HIV-1 by inhibiting E3 ubiquitin ligase activity

通过抑制 E3 泛素连接酶活性特异性激活潜伏 HIV-1

基本信息

批准号：
9197394
负责人：
JOSEPH DOUGHERTY
金额：
$ 40.25万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-11-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197394
关键词：
Affect Bioavailable Biological Assay Bone Marrow Cell Culture System Cells Chemicals Collection Combined Modality Therapy Complex Development Drug Interactions Drug Kinetics Epigenetic Process Gene Expression Gene Expression Regulation Generations Genetic Transcription Glean Goals HIV-1 Health Highly Active Antiretroviral Therapy Human Immunotherapy Individual Infection Latent Virus Lead Libraries Life Literature Liver Maintenance Modeling Modification Molecular Weight Mus Patients Pattern Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Play Property Proteasome Inhibition Proteasome Inhibitor Quantitative Structure-Activity Relationship RNA Polymerase II RNA interference screen Regulation Reporting Role Safety Source Specificity Structure System Techniques Testing Therapeutic Thymus Gland Toxic effect Ubiquitin Validation Virus Virus Latency analog arm base chromatin remodeling cytotoxicity design drug development efficacy testing genome-wide high throughput screening improved in vivo insight latent virus activation memory CD4 T lymphocyte multicatalytic endopeptidase complex pharmacophore protein degradation research study scaffold small molecule small molecule inhibitor transcription factor ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): HIV-1 persists indefinitely in infected individuals including those successfully being treated with highly active antiretroviral therapy (HAART). Numerous studies indicate that latently infected long-lived memory CD4+ T cells are an important source of enduring infection. A strategy that is being actively pursued to eliminate the latent arm of the infection involves developing and employing drugs that act as antagonists of viral latency. To date, the latency antagonists that have been identified tend to lack a high degree of specificity. Moreover, the mechanism(s) underlying viral latency in patients is likely multifactorial. Therefore, it may be necessary to develop combination therapies possibly in conjunction with immunotherapy to ultimately eliminate the virus from patients. Drugs, which can activate latent virus with high specificity are likely to have fewer off-target effects and might b significantly less toxic in the context of combination therapy. The ubiquitin-proteasome system (UPS) has been shown to play an important role in gene regulation. A great deal of specificity is imparted to the UPS particularly by the E3 ubiquitin ligases, of which there are more than 600 in human cells. Preliminary studies indicate that the UPS is involved in maintaining HIV-1 latency since proteasome inhibitors (PIs) can activate latent virus. This has led to the hypothesis that there is a factor positively affecting HIV-1 gene expression that is targeted for proteasomal degradation in latently infected cells. Therefore, it should be possible to identify the factor and the specific E3 ligase that directs it turnover, leading to development of drugs that can specifically inhibit ubiquitylation of the positive factor activating latent virus. The R21 phase (Aims 1 and 2) of this proposal aims at identifying the positive factor and the specific E3 ligase targeting its turnover. Upon successful completion of the R21, the R33 phase (Aims 3 and 4) would involve: 1) developing an assay suitable for high-throughput screening (HTS), 2) carrying out a HTS with a library of over 200,000 diversified low molecular weight compounds, 3) characterizing hits and selecting lead compounds, and 4) conducting lead optimization to improve the potency, selectivity, and pharmaceutical properties of lead compounds, aimed at the identification of an orally available Development Candidate.

描述（由申请人提供）：在受感染的个体中无限期地存在HIV-1，包括成功接受高度活性抗逆转录病毒疗法（HAART）的人。大量研究表明，潜在感染的长期记忆CD4+ T细胞是持久感染的重要来源。积极采取的消除感染潜在部门的策略涉及开发和使用作为病毒潜伏期的拮抗剂的药物。迄今为止，已确定的延迟拮抗剂往往缺乏高度的特异性。此外，患者的基本病毒潜伏期可能是多因素的。因此，可能有必要与免疫疗法结合开发组合疗法，以最终从患者中消除病毒。可以激活具有高特异性的潜在病毒的药物可能具有更少的脱靶作用，并且在组合疗法的背景下，毒性可能会大大减少。泛素 - 蛋白酶体系统（UPS）已显示在基因调节中起重要作用。尤其是E3泛素连接酶，将大量的特异性赋予了UPS，其中人类细胞中有600多个。初步研究表明，由于蛋白酶体抑制剂（PIS）可以激活潜在病毒，因此UPS参与了维持HIV-1潜伏期。这导致了这样的假设，即存在一个因子积极影响HIV-1基因表达的因素，该因素针对的是潜在感染细胞的蛋白酶体降解。因此，应该可以识别因素和指导其营业额的特定E3连接酶，导致可以特异性抑制积极因子激活潜在病毒的泛素化的药物的发展。该提案的R21阶段（目标1和2）旨在确定针对其营业额的正因素和特定的E3连接酶。 Upon successful completion of the R21, the R33 phase (Aims 3 and 4) would involve: 1) developing an assay suitable for high-throughput screening (HTS), 2) carrying out a HTS with a library of over 200,000 diversified low molecular weight compounds, 3) characterizing hits and selecting lead compounds, and 4) conducting lead optimization to improve the potency, selectivity, and pharmaceutical properties of lead compounds,旨在确定口服开发候选人。