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：
8915329
负责人：
Garland Ross Marshall
金额：
$ 5万
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/8915329
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：组蛋白脱乙酰基酶（HDAC）同工型的选择性抑制剂 - 为了消除HIV阳性患者的感染，必须清除潜在病毒储存剂以使感染细胞易于抗性病毒。 HDAC3似乎是负责模型细胞系中HIV潜伏期的主要HDAC，HDAC3的特定抑制剂应克服这些感染细胞的潜伏期，以使其暴露于抗病毒疗法中。然而，尚不清楚HDAC3的特定抑制剂是否由于缺乏同质性而有效地针对从恶毒患者中分离出的潜伏细胞。 HIV基因组的DNA整合是与任何有效根除所需的HDAC抑制剂的治疗时间，目前尚不清楚，非特异性表观遗传药物的副作用是一个明显的关注。磷灰素是典型的HDAC抑制剂（HDACIS），在这种情况下显示了同工型的选择性，在这种情况下为HDAC3，但仅表现出3倍歧视对HDAC2，而HDAC2与HDAC8相比11倍。阿匹维蛋白中的环状四肽头组是HDAC3的特异性来源，并且与Marshall Lab的主要研究兴趣相吻合，即使用受约束的环粒肽作为分子识别的探针。已经组织了一支由HDAC潜伏期中HDAC抑制剂设计，合成和表征的国际专家团队，以生成HDAC同工型的特定抑制剂，从HDAC3开始，从HDAC3开始潜在地消除艾滋病。