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

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.
项目总结

项目成果

期刊论文数量(0)
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专利数量(0)

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LARS ECKMANN其他文献

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{{ 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:
San Diego Digestive Diseases Research Center
圣地亚哥消化疾病研究中心
  • 批准号:
    10395968
  • 财政年份:
    2019
  • 资助金额:
    $ 64.84万
  • 项目类别:
San Diego Digestive Diseases Research Center
圣地亚哥消化疾病研究中心
  • 批准号:
    10617213
  • 财政年份:
    2019
  • 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:
Pilot and Feasibility Program
试点和可行性计划
  • 批准号:
    10395974
  • 财政年份:
    2019
  • 资助金额:
    $ 64.84万
  • 项目类别:
Pilot and Feasibility Program
试点和可行性计划
  • 批准号:
    10617225
  • 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:

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