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.

项目概要 阴道毛滴虫是最常见的非病毒性传播感染的病原体 全球每年报告新病例超过 2.5 亿，美国报告新病例 5-700 万。更多的 美国人感染这种寄生虫的情况比感染任何其他真核病原体的情况要多。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。同类药物中只有两种获得 FDA 批准用于治疗：甲硝唑 和替硝唑。尽管通常有效，但相当一部分患者会出现治疗失败的情况（1- 17%），并且这些药物有很大的责任，当由唯一的人给予时会产生中度至严重的不良反应 批准的口服途径治疗滴虫病。鉴于其患病率及其与多种疾病结果的关联， 随着耐药菌株的增加，迫切需要针对阴道毛滴虫的新抗菌药物。我们 在初步研究中发现蛋白酶体的抑制剂，这是一种重要的细胞机制 降解和回收细胞蛋白，有效杀灭阴道毛滴虫，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作为 治疗滴虫病的新治疗选择。我们将进行全细胞活性筛选 几个明确定义的蛋白酶体抑制剂文库，用于识别最有效的命中，确认命中 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功效 滴虫感染。总之，该项目在几个关键方面都很重要且具有创新性，包括 滴虫病的适应症、蛋白酶体作为寄生虫的新药物靶标、全细胞的使用 筛选和明确的、有针对性的化学库，全细胞筛选的补充 机械生化研究，重点关注局部给药作为一种新型治疗方法 为了感染。这些研究将由杰出的多学科研究团队进行 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。这种广泛的专业知识将有助于实现开发新类别的项目目标 有效的滴虫酸剂。