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

• 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
• 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

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：组蛋白去乙酰化酶（HDAC）亚型的选择性抑制剂——为了消除HIV阳性患者的感染，必须清除潜伏的病毒库，使感染细胞对抗病毒药物敏感。在模型细胞系中，HDAC3似乎是导致HIV潜伏期的主要HDAC，一种特定的HDAC3抑制剂应该克服这些感染细胞中的潜伏期，以便使它们暴露于抗病毒治疗。然而，目前尚不清楚特异性的HDAC3抑制剂是否对从病毒血症患者分离的潜伏期细胞有效，因为其位置缺乏同质性