Targeting host deubiquitinases for broad spectrum anti-infective therapy

靶向宿主去泛素酶进行广谱抗感染治疗

基本信息

  • 批准号:
    8854184
  • 负责人:
  • 金额:
    $ 46.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-07-01 至 2017-06-30
  • 项目状态:
    已结题

项目摘要

There is an urgent need for new therapeutics that effectively target drug-resistant microbes and pathogens that currently have no treatment options. Noroviruses cause an estimated 23 million infections and over half of all food-borne gastroenteritis outbreaks in the US every year but no antivirals or vaccines exist to treat or prevent infections. Listeria monocytogenes is another food-borne pathogen with a high fatality rate of 20- 25%, responsible for the recent cantaloupe-associated outbreak. Rapid diagnosis of a specific pathogen during outbreaks is often challenging. Thus, there is a compelling rationale for the development of broad-spectrum therapeutics for early and effective treatment of infectious diseases. One approach towards that goal is to develop “anti- infective” compounds that target host-encoded proteins critical during infection of multiple microbes. We find that a small molecule, WP1130 (WP) and related compounds, exhibit anti-infective activity against multiple classes of pathogens, including several category B pathogens: bacteria (MRSA, Listeria monocytogenes, Salmonella enterica serovar Typhimurium), viruses (murine and human norovirus, encephalomyocarditis virus, Sindbis virus, La Crosse virus), and an apicomplexan parasite (Toxoplasma gondii). Our initial studies demonstrate that WP inhibits a subset of host deubiquitinases (DUBs) resulting in the accumulation of ubiquitinated proteins in cells, but does not directly affect pathogens outside the host. Ubiquitin is a eukaryotic low molecular weight polypeptide that acts as a post-translational regulatory switch when covalently linked to target proteins. Studies of WP analogs hold vital clues for the development of novel therapeutics that may effectively contain pathogens by interfering with key interactions between host and microbe. Ubiquitination and deubiquination of host targets play critical roles in many different microbial infections. We therefore hypothesize that WP treatment selectively inhibits key DUBs exploited by microbial pathogens, thereby limiting infection. We will use murine norovirus and L. monocytogenes as two unrelated pathogens with established small animal models of infection to define DUB targets that mediate the anti-infective effects of WP. Our goal is to advance the lead compound towards an investigational new drug (IND) application. We therefore propose the following specific aims: (1) Determine target DUBs of WP that mediate anti-infective activity, (2) Test a SAR series of WP in vitro to identify lead compounds, and (3) Test lead compounds for in vivo efficacy. This application aims to develop a broad-spectrum anti-infective therapeutic effective against many pathogens including multiple category B agents.
迫切需要有效针对耐药的新疗法

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 }}

Mary O'Riordan其他文献

Mary O'Riordan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('Mary O'Riordan', 18)}}的其他基金

Mitochondrial stress shapes host responses to bacterial infection
线粒体应激塑造宿主对细菌感染的反应
  • 批准号:
    10317161
  • 财政年份:
    2021
  • 资助金额:
    $ 46.65万
  • 项目类别:
Mitochondrial stress shapes host responses to bacterial infection
线粒体应激塑造宿主对细菌感染的反应
  • 批准号:
    10413242
  • 财政年份:
    2021
  • 资助金额:
    $ 46.65万
  • 项目类别:
Mitochondrial stress shapes host responses to bacterial infection
线粒体应激塑造宿主对细菌感染的反应
  • 批准号:
    10616749
  • 财政年份:
    2021
  • 资助金额:
    $ 46.65万
  • 项目类别:
Mechanisms of host defense against membrane damage by pore-forming toxins
宿主防御成孔毒素膜损伤的机制
  • 批准号:
    8699346
  • 财政年份:
    2013
  • 资助金额:
    $ 46.65万
  • 项目类别:
Targeting host deubiquitinases for broad spectrum anti-infective therapy
靶向宿主去泛素酶进行广谱抗感染治疗
  • 批准号:
    8389503
  • 财政年份:
    2012
  • 资助金额:
    $ 46.65万
  • 项目类别:
Mobilization of lysosome anti-microbial defenses by the unfolded protein response
通过未折叠的蛋白质反应动员溶酶体抗微生物防御
  • 批准号:
    8519298
  • 财政年份:
    2012
  • 资助金额:
    $ 46.65万
  • 项目类别:
Mobilization of lysosome anti-microbial defenses by the unfolded protein response
通过未折叠的蛋白质反应动员溶酶体抗微生物防御
  • 批准号:
    8364443
  • 财政年份:
    2012
  • 资助金额:
    $ 46.65万
  • 项目类别:
Targeting host deubiquitinases for broad spectrum anti-infective therapy
靶向宿主去泛素酶进行广谱抗感染治疗
  • 批准号:
    8485542
  • 财政年份:
    2012
  • 资助金额:
    $ 46.65万
  • 项目类别:
Targeting host deubiquitinases for broad spectrum anti-infective therapy
靶向宿主去泛素酶进行广谱抗感染治疗
  • 批准号:
    8891354
  • 财政年份:
    2012
  • 资助金额:
    $ 46.65万
  • 项目类别:
Use of host derived lipoate by Listeria monocytogenes
单核细胞增生李斯特菌使用宿主来源的硫辛酸
  • 批准号:
    7050534
  • 财政年份:
    2005
  • 资助金额:
    $ 46.65万
  • 项目类别:

相似海外基金

Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
  • 批准号:
    495434
  • 财政年份:
    2023
  • 资助金额:
    $ 46.65万
  • 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
  • 批准号:
    10642519
  • 财政年份:
    2023
  • 资助金额:
    $ 46.65万
  • 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
  • 批准号:
    10586596
  • 财政年份:
    2023
  • 资助金额:
    $ 46.65万
  • 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
  • 批准号:
    10590479
  • 财政年份:
    2023
  • 资助金额:
    $ 46.65万
  • 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
  • 批准号:
    23K06011
  • 财政年份:
    2023
  • 资助金额:
    $ 46.65万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
  • 批准号:
    10682117
  • 财政年份:
    2023
  • 资助金额:
    $ 46.65万
  • 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
  • 批准号:
    10708517
  • 财政年份:
    2023
  • 资助金额:
    $ 46.65万
  • 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
  • 批准号:
    10575566
  • 财政年份:
    2023
  • 资助金额:
    $ 46.65万
  • 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
  • 批准号:
    23K15696
  • 财政年份:
    2023
  • 资助金额:
    $ 46.65万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
  • 批准号:
    23K15867
  • 财政年份:
    2023
  • 资助金额:
    $ 46.65万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了