Selective proteasome inhibitors for trichomoniasis

项目摘要 阴道毛滴虫是最常见的非病毒性性传播感染的病原体， 全球每年报告的新增病例为2.5亿例，美国为500万至700万例。更多 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、滴虫病会增加不良妊娠结局、艾滋病毒传播和 宫颈癌和前列腺癌。只有两种相同类别的药物获得FDA批准用于治疗，即甲硝唑 和替硝唑。虽然治疗通常有效，但相当一部分患者会出现治疗失败(1- 17%)，并且这些药物有很大的责任，当仅由 经批准的滴虫病口服途径。考虑到它的流行，它与多种疾病结局的关联， 随着耐药菌株的增加，迫切需要新的抗阴道毛滴虫药物。我们 在初步研究中发现，蛋白酶体的抑制剂，一种重要的细胞机制， 降解和回收细胞蛋白质，有效杀灭阴道毛滴虫，克服对甲硝唑的耐药性。 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作为一种 滴虫病治疗的新选择。我们将进行全细胞活动筛选 几个定义良好的蛋白酶体抑制剂文库来识别最有效的HITS，确认HITS 灭活寄生虫中的靶标，并探索最佳化合物在小鼠模型中的体内疗效 滴虫感染。总而言之，该项目在几个关键方面都是重要的和创新的，包括 滴虫病的适应症，蛋白酶体作为寄生虫新的药物靶点，使用全细胞 筛选和定义明确的靶向化学库，补充全细胞筛选 机械性生化研究，并将重点放在局部给药作为一种新的治疗方法上 治疗感染的药物。研究将由一个杰出的多学科研究团队进行， 在寄生虫学、抗菌药物开发、蛋白酶体生物学和医学方面的互补专业知识 化学反应。这些广泛的专业知识将有助于实现开发一个新班级的项目目标 强大的滴虫杀菌剂。

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.