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
- 来源:
- 关键词:AffectAnimal ModelAnti-Infective AgentsAntiviral AgentsBacteriaBacteriologyBiochemistryBiological AssayCantaloupesCategoriesCellsChemicalsCommunicable DiseasesDevelopmentDiagnosisDisease OutbreaksDrug KineticsDrug resistanceEarly treatmentEconomicsEncephalomyocarditis virusEnzymesExhibitsFutureGastroenteritisGoalsHumanIn VitroInfectionInfection preventionInfectious AgentInjection of therapeutic agentInvestigational New Drug ApplicationLa Crosse virusLeadLinkListeriaListeria monocytogenesLiver MicrosomesMediatingMicrobeModelingMolecular WeightMorbidity - disease rateMusNorovirusOrganismParasitesPharmaceutical ChemistryPharmacologyPhasePlayPositioning AttributeProteinsProteomicsPublic HealthResearchRoleSalmonella entericaSeriesSindbis VirusSolubilityStructure-Activity RelationshipTestingTherapeuticToxic effectToxoplasma gondiiUbiquitinUbiquitinationUnited StatesVaccinesViral GastroenteritisVirusWarWaterage groupanalogantimicrobialbasecellular targetingcytotoxicitydrug developmentdrug resistant bacteriaeffective therapyfoodbornefoodborne illnessfoodborne infectionfoodborne pathogenin vivoinhibitor/antagonistmethicillin resistant Staphylococcus aureusmicrobialmortalitynovelnovel therapeuticspathogenpolypeptidepre-clinicalprogramsrapid diagnosissmall moleculetherapeutic developmenttherapeutic targetvirology
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.
迫切需要有效针对抗药性的新疗法。
目前没有治疗选择的微生物和病原体。诺如病毒导致
估计有2300万人感染,超过一半的食源性胃肠炎暴发
美国每年都有这种病毒,但目前还没有抗病毒药物或疫苗来治疗或预防感染。
单核细胞增多性李斯特菌是另一种食源性致病菌,致死率高达20%-
25%,对最近与哈密瓜有关的疫情负有责任。快速诊断一种
暴发期间的特定病原体通常是具有挑战性的。因此,有一个令人信服的
开发早期有效的广谱疗法的理论基础
传染病的治疗。实现这一目标的一种方法是开发“反
以宿主编码的蛋白质为靶标的具有感染性的化合物
多种微生物。我们发现一种小分子,WP1130(WP)和相关的
化合物对多种病原体表现出抗感染活性,包括
几种B类病原体:细菌(MRSA、单核细胞增生性李斯特菌、沙门氏菌
肠道病毒(鼠伤寒沙门氏菌)、病毒(鼠和人诺如病毒、
脑心肌炎病毒、辛德比斯病毒、拉克罗斯病毒)和心尖复合体
寄生虫(弓形虫)。我们的初步研究表明可湿性粉剂抑制了一个子集
宿主去泛素酶(DUBS)导致泛素化蛋白在
细胞,但不直接影响寄主以外的病原体。泛素是一种真核生物
低分子量多肽在以下情况下充当翻译后调节开关
与目标蛋白共价连接。对可湿性粉剂类似物的研究为
通过干扰有效抑制病原体的新疗法的开发
与宿主和微生物之间的关键相互作用有关。泛素化和去泛素化
宿主靶标在许多不同的微生物感染中起着关键作用。因此,我们
假设可湿性粉剂治疗选择性地抑制由
微生物病原体,从而限制感染。我们将使用小鼠诺沃克病毒和L.
作为两种无关病原体的单核细胞增多症与已建立的小动物模型
确定介导可湿性粉剂抗感染作用的复制靶点。我们的目标是
将先导化合物推向研究性新药(IND)应用。
因此,我们提出了以下具体目标:(1)确定可湿性粉剂的目标配音
介导抗感染活性,(2)体外检测一系列可湿性粉剂的SAR以鉴定铅
以及(3)测试先导化合物的体内疗效。此应用程序旨在
开发对多种病原体有效的广谱抗感染治疗
包括多个B类特工。
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