DISCOVERY OF NEW THERAPEUTICS FOR DRUG-FREE REMISSION OF HIV

发现无药物缓解艾滋病毒的新疗法

基本信息

批准号：
8652488
负责人：
Garland Ross Marshall
金额：
$ 39.86万
依托单位：
WASHINGTON UNIVERSITY
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：
2013-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8652488
关键词：
Acetylation Acquired Immunodeficiency Syndrome Active Sites Adverse effects Affinity Amides Animal Model Antiviral Agents Binding Biological Assay CD4 Positive T Lymphocytes Cell Line Cell model Cells Clinical Trials Commit Complex Computer Simulation DNA Double Strand Break DNA Integration Data Development Discrimination Disease remission Disulfiram Dose Epigenetic Process Evaluation Exhibits Feedback Functional disorder Gene Expression Generations Genetic Genetic Transcription Goals Government HDAC2 gene HDAC3 gene HIV HIV Genome HIV Protease HIV Protease Inhibitors HIV Seropositivity HIV-1 Histone Deacetylase Histone Deacetylase Inhibitor Homology Modeling Individual Infection Interleukin-7 International Length Libraries Location Mammalian Cell Marshal Modeling Molecular Mutagens Patients Persons Pharmaceutical Preparations Poland Protease Inhibitor Protein Isoforms Protein Kinase C Publishing Quantitative Structure-Activity Relationship Research Role Signal Pathway Signal Transduction Source Specificity Structure System T-Lymphocyte Testing Therapeutic Transferase Tropism Universities Valproic Acid Viral Viremia Vorinostat Washington Zinc antiretroviral therapy apicidin base bryostatin clinically relevant combinatorial design improved inhibitor/antagonist interest macrophage molecular recognition novel therapeutics public health relevance purge scalpel screening tat Protein virtual

项目摘要

DESCRIPTION (provided by applicant): HIV latency: Selective Inhibitors of Histone Deacetylase (HDAC) Isoforms - In order to eliminate infection in HIV-positive patients, latent viral reservoirs must be purged to render infected cells susceptible to antivirals. HDAC3 appears to be the primary HDAC responsible for HIV latency in model cell lines, and a specific inhibitor of HDAC3 should overcome latency in these infected cells in order to expose them to antiviral therapeutics. It is not clear, however, that a specific inhibitor of HDAC3 would be effective against latency cells isolated from aviremic patients due to lack of homogeneity in the location of DNA integration of the HIV genome As the length of treatment with any HDAC inhibitor needed for effective eradication is unknown at present, side effects from non-specific epigenetic drugs is an obvious concern. Apicidin is typical of HDAC inhibitors (HDACIs) that show selectivity for an isoform, in this case HDAC3, but exhibit only 3-fold discrimination vs. HDAC2 and 11-fold vs. HDAC8. The cyclic tetrapeptide headgroup in apicidin is a source of specificity for HDAC3 and coincides with a major research interest of the Marshall lab, namely the use of constrained cyclictetrapeptides as probes of molecular recognition. An international team of experts in design, synthesis and characterization of HDAC inhibitors in overcoming HIV latency has been organized to generate specific inhibitors of HDAC isoforms, starting with HDAC3 for the potential eradication of AIDS.

描述（由申请人提供）： HIV 潜伏期：组蛋白脱乙酰酶 (HDAC) 异构体的选择性抑制剂 - 为了消除 HIV 阳性患者的感染，必须清除潜伏病毒库，使受感染的细胞对抗病毒药物敏感。 HDAC3 似乎是模型细胞系中 HIV 潜伏期的主要 HDAC，HDAC3 的特定抑制剂应该克服这些受感染细胞中的潜伏期，以便使它们接受抗病毒治疗。然而，由于 HDAC3 的位置缺乏同质性，目前尚不清楚 HDAC3 的特异性抑制剂是否能有效对抗从无病毒血症患者中分离出的潜伏细胞。 HIV 基因组的 DNA 整合由于目前尚不清楚有效根除任何 HDAC 抑制剂所需的治疗时间，因此非特异性表观遗传药物的副作用一个明显的担忧。 Apicidin 是典型的 HDAC 抑制剂 (HDACIs)，对异构体（在本例中为 HDAC3）表现出选择性，但与 HDAC2 相比仅表现出 3 倍的选择性，与 HDAC8 相比仅表现出 11 倍的选择性。 apicidin 中的环状四肽头基是 HDAC3 特异性的来源，并且与 Marshall 实验室的主要研究兴趣相一致，即使用受限环状四肽作为分子识别探针。一个由设计、合成和表征 HDAC 抑制剂以克服 HIV 潜伏期的国际专家组成的团队已经组织起来，以产生 HDAC 同工型的特异性抑制剂，从 HDAC3 开始，有可能根除艾滋病。