Selective proteasome inhibitors for trichomoniasis

滴虫病的选择性蛋白酶体抑制剂

• 批准号: 9806764
• 负责人: LARS ECKMANN
• 金额: $ 23.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9806764
• 关键词: Adverse effects; American; Annual Reports; Antiparasitic Agents; Biochemical; Biological Assay; Biology; Case Study; Cells; Cellular Assay; Complement; Data; Disease Outcome; Drug resistance; Enzymes; FDA approved; Genitourinary System Infection; HIV; Human; Immune; Infection; Interdisciplinary Study; Libraries; Malignant neoplasm of cervix uteri; Malignant neoplasm of prostate; Mediating; Metronidazole; Metronidazole resistance; Modeling; Monitor; Oral; Oral Administration; Parasites; Parasitology; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Prevalence; Proteasome Inhibitor; Proteins; Recycling; Risk; Route; Sexually Transmitted Diseases; Tinidazole; Topical application; Treatment Failure; Trichomonas Infections; Trichomonas vaginalis; United States; Vagina; adverse pregnancy outcome; antimicrobial; antimicrobial drug; base; cytotoxicity; drug development; effective therapy; in vitro Assay; in vivo; in vivo Model; inhibitor/antagonist; innovation; mouse model; multicatalytic endopeptidase complex; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; pathogen; resistant strain; screening; small molecule libraries; therapy resistant; transmission process; urogenital tract

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.

项目摘要 阴道毛毛虫是最常见的，非病毒性传播感染的原因 > 2.5亿新案件每年在全球报告，在美国举行5-7百万个案件。更多的 与任何其他真核病原体相比，美国人感染了这种寄生虫。除了感染 泌尿生殖道，滴虫病增加了不良妊娠结局的风险，HIV传播和 宫颈癌和前列腺癌。同一类中只有两种药物是FDA批准的，用于治疗，甲硝唑 和替替唑。尽管通常有效，但在很大一部分患者中会发生治疗失败（1- 17％），药物具有明显的负债 经过批准的毛瘤病的口腔途径。鉴于其患病率是与多种疾病结局的关联， 迫切需要抗药菌株的抗药性菌株，迫切需要针对阴道的新抗菌药物。我们 在初步研究中发现了蛋白酶体的抑制剂，这是一种必需的细胞机制 细胞蛋白的降解和回收利用，有效地杀死阴道链球菌并克服甲硝唑的耐药性。 基于这些有趣的发现，该项目的总体目标是将蛋白酶体抑制剂作为一种 用于治疗毛诺病的新型治疗选择。我们将执行全细胞活动屏幕 蛋白酶体抑制剂的几个定义明确的库，以识别最有效的命中，确认命中 使寄生虫中的靶标失活，并探索鼠模型中最佳化合物的体内功效 Trichomonad感染。该项目在几个关键方面都很重要和创新，包括 曲奇诺病的指示，蛋白酶体是寄生虫中的一种新药物靶标的，使用了全细胞 筛选和定义明确的，有针对性的化学文库，与全细胞筛查的补充 机械生化研究，并将重点放在局部药物给药作为一种新型治疗方法 为了感染。这些研究将由一个杰出的多学科研究团队与 寄生虫学，抗菌药物开发，蛋白酶体生物学和药用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以开发新的班级 有效的三核剂。