Towards HIV eradication using a novel Tat inhibitor

使用新型 Tat 抑制剂消灭 HIV

基本信息

  • 批准号:
    8993241
  • 负责人:
  • 金额:
    $ 47.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-06-15 至 2020-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Antiretroviral therapy (ART) effectively blocks viral replication, although it fails to eradicate the virus. A small population of latently infected restng memory CD4+T cells still persists in patients on suppressive therapy. The most explored strategy for HIV eradication is dubbed "shock and kill", which attempts to purge the viral reservoir by reactivating the virus using anti-latency agents in the presence of ART. The expectation is that reactivation will prompt elimination of infected cells by cytopathic effects and/or by cytolytic T-lymphocyte lysis (1). This approach is challenging and has been unsuccessful thus far. Right now, we need new therapeutic agents that target different stages of the virus life cycle and limit latent HIV disease. The viral protein Tat binds HIV mRNA and promotes viral transcription. Compounds that block Tat activity have been highly sought after; however, none is yet in the clinic. We reported that Cortistatins, steroid-like alkaloids isolated from the marine sponge corticium simplex, represent a novel class of anti- Tat drug candidates. Didehydro-Cortistatin A (dCA) potently and selectively inhibits Tat-activity with no cellular associated toxicity (2). dCA binds specifically to the RNA-binding domain of Tat reducing HIV-1 RNA production in infected cultured and primary cells at an EC50 as low as 0.7 pM. Treatment of HIV-1 infected cells with dCA drives viral gene expression into an induced state of persistent deep latency in vitro, refractory to viral reactivation by the usual panel of activators (cytokines HDAC inhibitors, PKC activators). Discontinuation of dCA treatment does not result in viral rebound, suggesting the chromatin environment of the HIV promoter is epigenetically repressed. Importantly, dCA abrogates antigenic virus reactivation from latently infected CD4+T primary cells explanted from patients receiving suppressive ART. We propose an alternative approach to the "shock and kill" strategy. Specifically, using a Tat-inhibitor to target HIV-1 transcription rather than activating the endogenous latent reservoir, we propose to drive the residual transcription that occurs during ART into long-term latency or deep latency. A Tat-inhibitor combined with ART could reduce the size of the latent reservoir pool by blocking ongoing viral replication, reactivation and replenishment of the latent viral reservoir. Thus, the latent pool of cells in an infected individual would be stabilized, and death of the long-lived infected memory T-cells would result in a continuous decay of this pool over time, possibly culminating in the long-awaited sterilizing cure. Here we propose to: 1) fully characterize the molecular epigenetic events set in place at the HIV promoter in the presence of dCA and how these modifications impact HIV transcriptional activity; 2) establish a robust primary cellular model of latency that wll allow for confirmation of dCA mediated epigenetic modifications and 3) understand the molecular mechanism of viral resistance to dCA.


项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Susana T Valente其他文献

Potent suppression of HIV viral replication by a novel inhibitor of Tat
  • DOI:
    10.1186/1742-4690-9-s1-o11
  • 发表时间:
    2012-05-25
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Guillaume Mousseau;Mark A Clementz;Wendy N Bakeman;Nisha Nagarsheth;Michael Cameron;Jun Shi;Phil Baran;Rémi Fromentin;Nicolas Chomont;Susana T Valente
  • 通讯作者:
    Susana T Valente

Susana T Valente的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Susana T Valente', 18)}}的其他基金

Development and characterization of HIV-1 Tat degraders
HIV-1 Tat 降解剂的开发和表征
  • 批准号:
    10483950
  • 财政年份:
    2022
  • 资助金额:
    $ 47.4万
  • 项目类别:
Host factors regulating HIV latency and reactivation
调节HIV潜伏期和再激活的宿主因素
  • 批准号:
    10516096
  • 财政年份:
    2021
  • 资助金额:
    $ 47.4万
  • 项目类别:
Host factors regulating HIV latency and reactivation
调节HIV潜伏期和再激活的宿主因素
  • 批准号:
    10427641
  • 财政年份:
    2021
  • 资助金额:
    $ 47.4万
  • 项目类别:
Validation and characterization of Tat inhibitors identified through HTS
通过 HTS 鉴定的 Tat 抑制剂的验证和表征
  • 批准号:
    10258019
  • 财政年份:
    2021
  • 资助金额:
    $ 47.4万
  • 项目类别:
Validation and characterization of Tat inhibitors identified through HTS
通过 HTS 鉴定的 Tat 抑制剂的验证和表征
  • 批准号:
    10468812
  • 财政年份:
    2021
  • 资助金额:
    $ 47.4万
  • 项目类别:
Host factors regulating HIV latency and reactivation
调节HIV潜伏期和再激活的宿主因素
  • 批准号:
    10403317
  • 财政年份:
    2021
  • 资助金额:
    $ 47.4万
  • 项目类别:
Host factors regulating HIV latency and reactivation
调节HIV潜伏期和再激活的宿主因素
  • 批准号:
    10591707
  • 财政年份:
    2021
  • 资助金额:
    $ 47.4万
  • 项目类别:
Validation and characterization of Tat inhibitors identified through HTS
通过 HTS 鉴定的 Tat 抑制剂的验证和表征
  • 批准号:
    10591875
  • 财政年份:
    2021
  • 资助金额:
    $ 47.4万
  • 项目类别:
Identification and characterization of chromatin regulators of HIV-1 latency
HIV-1 潜伏期染色质调节因子的鉴定和表征
  • 批准号:
    9975693
  • 财政年份:
    2018
  • 资助金额:
    $ 47.4万
  • 项目类别:
Identification and characterization of chromatin regulators of HIV-1 latency
HIV-1 潜伏期染色质调节因子的鉴定和表征
  • 批准号:
    10591851
  • 财政年份:
    2018
  • 资助金额:
    $ 47.4万
  • 项目类别:

相似国自然基金

Iboga alkaloids骨架导向的不对称串联反应构建吖庚环并[4,5-b]吲哚及其在全合成中的应用
  • 批准号:
    21801032
  • 批准年份:
    2018
  • 资助金额:
    26.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Investigation on naphthylisoquinoline alkaloids as potential antiausterity chemotherapy for pancreatic cancer
萘基异喹啉生物碱作为胰腺癌潜在抗紧缩化疗的研究
  • 批准号:
    23K26797
  • 财政年份:
    2024
  • 资助金额:
    $ 47.4万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
CAREER: Chemoenzymatic Synthesis of Complex Polycyclic Alkaloids Enabled by A-Ketoglutarate Dependent Iron Enzymes
职业:通过 A-酮戊二酸依赖性铁酶实现复杂多环生物碱的化学酶法合成
  • 批准号:
    2338495
  • 财政年份:
    2024
  • 资助金额:
    $ 47.4万
  • 项目类别:
    Continuing Grant
Strategy Driven Synthesis of Complex Alkaloids
复杂生物碱的策略驱动合成
  • 批准号:
    2400232
  • 财政年份:
    2024
  • 资助金额:
    $ 47.4万
  • 项目类别:
    Standard Grant
Synthesis of guanidine alkaloids based on palladium catalyzed cyclization-carbonylation reactions.
基于钯催化环化-羰基化反应合成胍生物碱。
  • 批准号:
    23K06034
  • 财政年份:
    2023
  • 资助金额:
    $ 47.4万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Investigation on naphthylisoquinoline alkaloids as potential antiausterity chemotherapy for pancreatic cancer
萘基异喹啉生物碱作为胰腺癌潜在抗紧缩化疗的研究
  • 批准号:
    23H02104
  • 财政年份:
    2023
  • 资助金额:
    $ 47.4万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Anthropogenic change and disease susceptibility in poison frogs: identifying links with diet, skin alkaloids, and the microbiome
毒蛙的人为变化和疾病易感性:确定与饮食、皮肤生物碱和微生物组的联系
  • 批准号:
    2882384
  • 财政年份:
    2023
  • 资助金额:
    $ 47.4万
  • 项目类别:
    Studentship
Synthesis of Anticancer Alkaloids on Cancer Cells with Glycosylated Artificial Metalloenzymes
糖基化人工金属酶合成抗癌细胞生物碱
  • 批准号:
    22KJ1525
  • 财政年份:
    2023
  • 资助金额:
    $ 47.4万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Discovery of analgesic diterpenoid alkaloids from medicinal Aconitum plants using a metabolomic approach
使用代谢组学方法从药用乌头植物中发现镇痛二萜生物碱
  • 批准号:
    10629875
  • 财政年份:
    2023
  • 资助金额:
    $ 47.4万
  • 项目类别:
Excellence in Research: Biosynthetic investigation of manzamine class alkaloids
卓越研究:曼扎明类生物碱的生物合成研究
  • 批准号:
    2302454
  • 财政年份:
    2023
  • 资助金额:
    $ 47.4万
  • 项目类别:
    Standard Grant
Transition Metal-Catalyzed Reaction Development Toward the Synthesis of Alkaloids
过渡金属催化生物碱合成反应的进展
  • 批准号:
    2247315
  • 财政年份:
    2023
  • 资助金额:
    $ 47.4万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了