Selective proteasome inhibitors for trichomoniasis

项目摘要 阴道毛滴虫是最常见的非病毒性传播感染的病原体， 全球每年报告的新病例超过2.5亿例，美国有500万至700万例。更 美国人感染这种寄生虫的人数比感染其他任何真核病原体的人数都多。除了感染 泌尿生殖道，滴虫病增加不良妊娠结局，艾滋病毒传播的风险， 宫颈癌和前列腺癌。只有两种同类药物被FDA批准用于治疗，甲硝唑 和替硝唑。尽管总体上有效，但治疗失败发生在相当一部分患者中（1- 10%）。 17%），并且药物具有显著的负债，当由唯一的药物给药时，具有中度至重度的不良反应。 经批准，用于滴虫病的口服途径。考虑到它的流行程度，它与多种疾病结果的关系， 以及耐药菌株的增加，新的抗T.流浪汉是迫切需要的。我们 在初步研究中发现，蛋白酶体的抑制剂，一个重要的细胞机制， 细胞蛋白质的降解和再循环，有效地杀死T.克服甲硝唑耐药性。 基于这些有趣的发现，该项目的总体目标是开发蛋白酶体抑制剂， 治疗滴虫病的新的治疗选择。我们将进行全细胞活性筛选， 几个定义明确的蛋白酶体抑制剂文库，以确定最有效的命中，证实命中， 研究寄生虫中的靶标，并探索最佳化合物在小鼠模型中的体内功效 毛滴虫感染总之，该项目在几个关键方面都很重要，也很创新，包括 毛滴虫病的适应症，蛋白酶体作为寄生虫中的新药物靶点，全细胞 筛选和明确定义的靶向化学文库， 机制的生化研究，并侧重于局部给药作为一种新的治疗方法 因为感染研究将由一个杰出的跨专业研究团队进行， 在寄生虫学、抗微生物药物开发、蛋白酶体生物学和医学方面的互补专业知识 化学.这种广泛的专业知识将有助于实现项目目标，开发一个新的类 强力的杀滴虫剂

Project Summary Trichomonas vaginalis is the causative agent of the most common, non-viral sexually-transmitted infection with >250 million new cases reported annually in the world and 5-7 million cases in the United States. More Americans are infected with this parasite than with any other eukaryotic pathogen. 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, metronidazole and tinidazole. Although generally effective, treatment failures occur in a substantial fraction of patients (1- 17%), and the drugs have significant liabilities, with moderate to severe adverse effects when given by the only approved, oral route for trichomoniasis. Given its prevalence, its association with multiple disease outcomes, and an increase in drug-resistant strains, new antimicrobials against T. vaginalis are urgently needed. We discovered in preliminary studies that inhibitors of the proteasome, an essential cellular machinery for the degradation and recycling of cell proteins, effectively kill T. vaginalis and overcome metronidazole resistance. Based on these intriguing findings, the project has the overall objective to develop proteasome inhibitors as a novel therapeutic option for the treatment of trichomoniasis. We will perform whole-cell activity screens of several well-defined libraries of proteasome inhibitors to identify the most potent hits, confirm that the hits inactivate the targets in the parasite, and explore the in vivo efficacy of the best compounds in murine models of trichomonad infection. Together, the project is important and innovative in several key aspects, including the indication of trichomoniasis, the proteasome as a new drug target in the parasite, the use of whole-cell screening and well-defined, targeted chemical libraries, complementation of whole-cell screening with mechanistic biochemical studies, and a focus on topical drug administration as a novel therapeutic approach for the infection. The studies will be conducted by an outstanding multi-disciplinary research team with complementary expertise in parasitology, antimicrobial drug development, proteasome biology, and medicinal chemistry. This broad expertise will be instrumental for achieving the project objective to develop a new class of potent trichomonacidal agents.