Proteasome inhibitors against mucosal protozoan pathogens

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。

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.