Proteasome inhibitors against mucosal protozoan pathogens
针对粘膜原生动物病原体的蛋白酶体抑制剂
基本信息
- 批准号:10367246
- 负责人:
- 金额:$ 64.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-22 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdverse effectsAppearanceBenignBiochemicalBiological AssayBiologyCell LineCellsChemistryCleaved cellClinicalCryoelectron MicroscopyDataDevelopmentDiseaseDisease OutcomeDrug KineticsDrug resistanceEncephalopathiesEvaluationFDA approvedFluorogenic SubstrateGenitourinary System InfectionHIVHela CellsHumanIn VitroIncidenceInfectionInvestigationLeadLibrariesMalignant neoplasm of cervix uteriMalignant neoplasm of prostateMammalian CellMeasuresMeningitisMetallic TastesMetronidazoleMicrobeModelingModificationMucous MembraneMusMuscle CrampNauseaNew AgentsOralOral AdministrationParasitesParasitic DiseasesParasitologyPatientsPeptide HydrolasesPeptidesPeripheral Nervous System DiseasesPharmaceutical ChemistryPharmaceutical PreparationsPrevalenceProteasome BindingProteasome InhibitorProtein Complex SubunitProteinsRecyclingResearch PersonnelResistanceResistance developmentResolutionRiskRouteSeveritiesSexual TransmissionStomachStructureSubstrate SpecificityTestingTherapeuticTinidazoleTopical applicationToxic effectToxicity TestsTreatment FailureTrichomonas InfectionsTrichomonas vaginalisVaginaWomanadverse pregnancy outcomeantimicrobialantimicrobial drugbasecytotoxicitydesigndrug candidatedrug developmenteffective therapyefficacy testingexperienceimprovedin vitro activityin vivoin vivo evaluationinhibitor/antagonistmenmouse modelmulticatalytic endopeptidase complexnew therapeutic targetnovelpathogenpeptide drugpreclinical studyprotein degradationreproductive tractresistant strainside effecttherapy resistanttransmission processurogenital tract
项目摘要
Project Summary
Trichomonas vaginalis is the causative agent of trichomoniasis, the most common, non-viral sexually-
transmitted disease, with 5-7 million cases in the U.S. and >200 million in the world each year. In addition to
infections of the urogenital tract, trichomoniasis increases the risk of adverse pregnancy outcomes, HIV
transmission, and cervical and prostate cancer. Only two drugs of the same class are FDA-approved for
treatment, the nitro drugs metronidazole and tinidazole. Although generally effective, treatment failures occur in
a substantial fraction of patients and the drugs have significant liabilities, with moderate to severe adverse
effects and poor compliance due to seemingly benign but common side effects such as metallic taste. Given its
prevalence, its association with multiple disease outcomes, and an increase in nitro drug-resistant strains, new
antimicrobials against T. vaginalis are urgently needed, particularly in women where infection can persist for
months or even years compared to generally less than ten days in men. In extensive preliminary studies, we
determined that inhibitors of the proteasome, an essential cellular machinery for the degradation and recycling
of cell proteins, kill T. vaginalis at sub-micromolar levels. Importantly, the inhibitors overcome nitro drug
resistance and are efficacious in a murine model of trichomonad infection. We have also isolated and
biochemically characterized proteasomes from T. vaginalis and human HeLa cells and found that they display
significant differences in their peptide substrate specificity, providing the rationale for designing new potent and
parasite-selective proteasome inhibitors. Based on these promising findings, the project has the overall
objective to develop novel proteasome inhibitors with greatly improved potency and selectivity for the treatment
of trichomoniasis. Using a hit compound with 50-fold selectivity, we will systematically develop T. vaginalis-
specific proteasome inhibitors using a comprehensive combination of medicinal chemistry efforts, functional
testing with multiple clinical strains of T. vaginalis, biochemical and structural investigations of the parasite
proteasomes, and efficacy and toxicity testing in murine infection models. We have assembled a superb team
of investigators with complementary expertise in parasitology, protease biology, antimicrobial drug
development, and medicinal and peptide chemistry. The team has the experience and track record to conduct
the critical pre-clinical studies to establish proteasome inhibitors as a new class of agents in the therapeutic
armamentarium against trichomoniasis.
项目摘要
阴道毛滴虫是滴虫病的病原体,最常见的,非病毒性的性-
每年在美国有5-7百万例,在世界上有超过2亿例。除了
泌尿生殖道感染,滴虫病增加不良妊娠结局的风险,艾滋病毒
以及宫颈癌和前列腺癌。只有两种同类药物被FDA批准用于
治疗,硝基药物甲硝唑和替硝唑。虽然一般有效,但治疗失败发生在
很大一部分患者和药物具有重大责任,
副作用和不良的依从性,由于看似良性,但常见的副作用,如金属味道。鉴于其
流行率,其与多种疾病的结果,并增加硝基耐药菌株,新的
抗T.迫切需要进行迷走神经检查,特别是在感染可能持续
几个月甚至几年,而男性通常不到十天。在广泛的初步研究中,我们
确定蛋白酶体的抑制剂,蛋白酶体是降解和回收的基本细胞机制,
细胞蛋白质,杀死T。亚微摩尔水平的迷走神经。重要的是,抑制剂克服了硝基药物
在毛滴虫感染的鼠模型中有效。我们还隔离了
对T. vaginal和人类HeLa细胞,发现它们显示,
它们在肽底物特异性上的显著差异,为设计新的有效的和
寄生虫选择性蛋白酶体抑制剂。基于这些令人鼓舞的发现,该项目具有总体的
目的开发新的蛋白酶体抑制剂,提高其治疗效果和选择性
滴虫病利用一个选择性高达50倍的目标化合物,我们将系统地开发T。迷走神经,
使用药物化学努力的综合组合,功能性,
用多种临床菌株的T.寄生虫的迷走性、生物化学和结构研究
蛋白酶体,以及在鼠感染模型中的功效和毒性测试。我们组建了一支优秀的队伍
在寄生虫学、蛋白酶生物学、抗菌药物
发展,医药和肽化学。该团队拥有丰富的经验和良好的记录,
关键的临床前研究,以建立蛋白酶体抑制剂作为一类新的药物,在治疗
抗滴虫病的医疗设备。
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 }}
LARS ECKMANN其他文献
LARS ECKMANN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('LARS ECKMANN', 18)}}的其他基金
Membrane-cloaked nanoparticles as mucosal vaccines against giardiasis
膜包裹纳米粒子作为贾第鞭毛虫病粘膜疫苗
- 批准号:
10495210 - 财政年份:2021
- 资助金额:
$ 64.84万 - 项目类别:
Proteasome inhibitors against mucosal protozoan pathogens
针对粘膜原生动物病原体的蛋白酶体抑制剂
- 批准号:
10674897 - 财政年份:2021
- 资助金额:
$ 64.84万 - 项目类别:
Membrane-cloaked nanoparticles as mucosal vaccines against giardiasis
膜包裹纳米粒子作为贾第鞭毛虫病粘膜疫苗
- 批准号:
10351416 - 财政年份:2021
- 资助金额:
$ 64.84万 - 项目类别:
Selective proteasome inhibitors for trichomoniasis
滴虫病的选择性蛋白酶体抑制剂
- 批准号:
9806764 - 财政年份:2019
- 资助金额:
$ 64.84万 - 项目类别:
High-potency nitro antimicrobials for topical treatment of trichomoniasis
用于局部治疗滴虫病的高效硝基抗菌剂
- 批准号:
9049219 - 财政年份:2016
- 资助金额:
$ 64.84万 - 项目类别:
Next-generation 5-nitro heterocyclic antimicrobials against mucosal protists
针对粘膜原生生物的下一代 5-硝基杂环抗菌剂
- 批准号:
8962082 - 财政年份:2015
- 资助金额:
$ 64.84万 - 项目类别:
相似海外基金
Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
- 批准号:
10591918 - 财政年份:2023
- 资助金额:
$ 64.84万 - 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
- 批准号:
23K15383 - 财政年份:2023
- 资助金额:
$ 64.84万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
- 批准号:
23H03556 - 财政年份:2023
- 资助金额:
$ 64.84万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
- 批准号:
23K17212 - 财政年份:2023
- 资助金额:
$ 64.84万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
- 批准号:
22H03519 - 财政年份:2022
- 资助金额:
$ 64.84万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
- 批准号:
563657-2021 - 财政年份:2022
- 资助金额:
$ 64.84万 - 项目类别:
Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10521849 - 财政年份:2022
- 资助金额:
$ 64.84万 - 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10671022 - 财政年份:2022
- 资助金额:
$ 64.84万 - 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
- 批准号:
10670918 - 财政年份:2022
- 资助金额:
$ 64.84万 - 项目类别:
Downsides of downhill: The adverse effects of head vibration associated with downhill mountain biking on visuomotor and cognitive function
速降的缺点:与速降山地自行车相关的头部振动对视觉运动和认知功能的不利影响
- 批准号:
2706416 - 财政年份:2022
- 资助金额:
$ 64.84万 - 项目类别:
Studentship