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: 9058087
• 负责人: Garland Ross Marshall
• 金额: $ 31.5万
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058087
• 关键词: Acetylation; Acquired Immunodeficiency Syndrome; Active Sites; Adverse effects; Affinity; Ames Assay; Amides; Animal Model; Antiviral Agents; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cell Line; Cell model; Cells; Clinical Trials; Complex; Computer Simulation; DNA Double Strand Break; DNA Integration; Data; Development; Discrimination; Disease remission; Disulfiram; Dose; Evaluation; Exhibits; Feedback; Functional disorder; Gene Expression; Generations; Genetic; Genetic Transcription; Goals; Government; HDAC2 gene; HDAC3 gene; HDAC8 gene; HIV; HIV Genome; HIV Protease; HIV Protease Inhibitors; HIV Seropositivity; HIV-1; HIV-1 protease; 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; 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; Viral reservoir; Viremia; Vorinostat; Washington; Zinc; antiretroviral therapy; apicidin; base; bryostatin; clinically relevant; combinatorial; design; epigenetic drug; 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：组蛋白脱乙酰酶(HDAC)亚型的选择性抑制物-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。HDAC3似乎是导致模型细胞株中HIV潜伏期的主要HDAC，HDAC3的特异性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HDAC3的特异性抑制剂对从无氧血症患者中分离出来的潜伏期细胞是否有效，因为其位置缺乏同质性 HIV基因组的DNA整合作为有效根除所需的任何HDAC抑制剂的治疗长度目前尚不清楚，非特异性表观遗传药物的副作用是 这是一个明显的担忧。Apicidin是典型的HDAC抑制剂(HDACIs)，它显示出对异构体的选择性，在这种情况下是HDAC3，但与HDAC2和HDAC8相比只有3倍的区别和11倍的区别。APICIDIN中的环四肽头基是HDAC3特异性的来源，也符合马歇尔实验室的一个主要研究兴趣，即使用受限的环四肽作为分子识别的探针。在设计、合成和表征用于克服艾滋病毒潜伏期的HDAC抑制剂方面，已经组织了一个国际专家小组，以产生特定的HDAC亚型抑制剂，从HDAC3开始，以潜在地根除艾滋病。

项目成果

Design and Synthesis of Simplified Largazole Analogues as Isoform-Selective Human Lysine Deacetylase Inhibitors.

• DOI: 10.1021/acs.jmedchem.5b01632
• 发表时间: 2016-01
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: D. Reddy;F. Ballante;Timothy Chuang;Adele Pirolli;B. Marrocco;G. Marshall

Design and synthesis of benzodiazepine analogs as isoform-selective human lysine deacetylase inhibitors.

作为异构体选择性人赖氨酸脱乙酰酶抑制剂的苯二氮卓类似物的设计和合成。

• DOI: 10.1016/j.ejmech.2016.12.032
• 发表时间: 2017
• 期刊: European journal of medicinal chemistry
• 影响因子: 6.7
• 作者: Reddy,DRajasekhar;Ballante,Flavio;Zhou,NancyJ;Marshall,GarlandR
• 通讯作者: Marshall,GarlandR

Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines.

• DOI: 10.1080/14756366.2020.1835883
• 发表时间: 2021-12
• 期刊: Journal of enzyme inhibition and medicinal chemistry
• 影响因子: 5.6
• 作者: Nencetti S;Cuffaro D;Nuti E;Ciccone L;Rossello A;Fabbi M;Ballante F;Ortore G;Carbotti G;Campelli F;Banti I;Gangemi R;Marshall GR;Orlandini E
• 通讯作者: Orlandini E