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: 8540688
• 负责人: Garland Ross Marshall
• 金额: $ 40.28万
• 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/8540688
• 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（由申请方提供）：HIV潜伏期：组蛋白脱乙酰酶（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。HDAC 3似乎是负责模型细胞系中HIV潜伏期的主要HDAC，HDAC 3的特异性抑制剂应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剂。然而，尚不清楚HDAC 3的特异性抑制剂是否能有效对抗从病毒血症患者分离的潜伏细胞，这是由于HDAC 3的位置缺乏均一性。 HIV基因组的DNA整合由于目前尚不清楚有效根除所需的任何HDAC抑制剂的治疗时间长度， 一个明显的担忧。Apicidin是典型的HDAC抑制剂（HDACI），其显示出对同种型（在这种情况下为HDAC 3）的选择性，但相对于HDAC 2仅表现出3倍的辨别力，相对于HDAC 8仅表现出11倍的辨别力。apicidin中的环状四肽头基是HDAC 3特异性的来源，并且与马歇尔实验室的主要研究兴趣一致，即使用受约束的环状四肽作为分子识别的探针。一个设计、合成和表征HDAC抑制剂以克服HIV潜伏期的国际专家小组已经组织起来，以产生HDAC亚型的特异性抑制剂，从HDAC 3开始，以潜在地根除艾滋病。