Proteasome inhibitors against mucosal protozoan pathogens

项目摘要 阴道毛滴虫是滴虫病的病原体，滴虫病是最常见的非病毒性- 传播性疾病，美国每年有500-700万例，世界每年有2亿例。除了……之外 泌尿生殖道感染、滴虫病增加不良妊娠结局的风险 传播，以及宫颈癌和前列腺癌。只有两种相同类别的药物是FDA批准的 治疗中，硝基类药物甲硝唑和替硝唑。虽然治疗通常有效，但治疗失败的情况发生在 相当一部分患者和药物有重大的责任，有中度到严重的不良反应 效果和依从性差，因为看似良性但常见的副作用，如金属味道。鉴于其 流行率及其与多种疾病结局的关联，以及硝基耐药菌株的增加，新的 迫切需要针对阴道毛滴虫的抗菌药，特别是在感染可持续 几个月甚至几年，而男性一般不到十天。在广泛的初步研究中，我们 确定了蛋白酶体的抑制物，蛋白酶体是降解和循环的基本细胞机制 在细胞蛋白质中，以亚微摩尔水平杀死阴道毛滴虫。重要的是，这些抑制剂克服了硝基药物 在滴虫感染的小鼠模型中是有效的。我们还隔离了 对阴道毛滴虫和人HeLa细胞的蛋白酶体进行了生化特征分析，发现它们表现出 它们在多肽底物专一性上的显著差异，为设计新的高效和 寄生虫选择性蛋白酶体抑制剂。基于这些有希望的发现，该项目总体上 目的开发新的蛋白酶体抑制剂，以提高治疗效果和选择性。 滴虫病。使用选择性50倍的Hit化合物，我们将系统地培养阴道毛滴虫- 利用药物化学作用的全面组合的特定蛋白酶体抑制剂，功能性 多株阴道毛滴虫临床株检测及生化和结构研究 蛋白酶体，以及小鼠感染模型的有效性和毒性测试。我们已经组建了一支一流的团队 在寄生虫学、蛋白酶生物学、抗菌药物方面具有互补专业知识的研究人员 发展，以及药物和多肽化学。团队有经验和跟踪记录来进行 建立蛋白酶体抑制剂作为一类新的治疗药物的关键临床前研究 抗滴虫病的药具。

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.