Proteasome inhibitors against mucosal protozoan pathogens

针对粘膜原生动物病原体的蛋白酶体抑制剂

基本信息

批准号：
10674897
负责人：
LARS ECKMANN
金额：
$ 64.84万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674897
关键词：
Acute Adverse effects Appearance Benign Biochemical Biological Assay Biology Cell Line Cells Chemistry Clinical Cryoelectron Microscopy Data Development Disease Disease Outcome Drug Kinetics Drug resistance Encephalopathies Evaluation FDA approved Fluorogenic Substrate Genitourinary System Infection HIV Hela Cells Human In Vitro Incidence Infection Investigation Lead Libraries Malignant neoplasm of cervix uteri Malignant neoplasm of prostate Mammalian Cell Measures Medicine Meningitis Metallic Tastes Metronidazole Microbe Modeling Modification Mucous Membrane Mus Muscle Cramp Nausea New Agents Oral Oral Administration Parasites Parasitic Diseases Parasitology Patients Peptide Hydrolases Peptides Peripheral Nervous System Diseases Pharmaceutical Chemistry Pharmaceutical Preparations Prevalence Proteasome Binding Proteasome Inhibitor Protein Complex Subunit Proteins Recycling Research Personnel Resistance Resistance development Resolution Risk Route Severities Sexual Transmission Sexually Transmitted Diseases Stomach Structure Substrate Specificity Testing Therapeutic Tinidazole Topical application Toxic effect Toxicity Tests Treatment Failure Trichomonas Infections Trichomonas vaginalis Vagina Woman adverse pregnancy outcome antimicrobial antimicrobial drug cytotoxicity design drug candidate drug development efficacy testing experience improved in vitro activity in vivo in vivo evaluation inhibitor men mouse model multicatalytic endopeptidase complex new therapeutic target novel pathogen peptide drug preclinical study protein degradation reproductive tract resistant strain side effect therapy resistant transmission process urogenital tract

项目摘要

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.

项目摘要 trichomonas vaginalis是滴虫病的病因，最常见的非病毒性 - 传播疾病，在美国有5-7百万例病例，全球含量为2亿。此外泌尿生殖道的感染，滴虫病增加了不良妊娠结局的风险，HIV 传播以及宫颈癌和前列腺癌。同一类中只有两种药物是FDA批准的治疗，硝基药物甲硝唑和替替唑。尽管通常有效，但治疗失败发生在大部分患者和药物具有明显的责任，中度至重度不良效果和依从性不佳，但由于似乎是良性的，但具有常见的副作用，例如金属味。鉴于它患病率，与多种疾病结局的关联，硝基抗药性菌株的增加，新迫切需要针对阴道的抗菌素，尤其是在感染可以持续存在的女性中几个月甚至几年的男性通常不到十天。在广泛的初步研究中，我们确定蛋白酶体的抑制剂，这是一种降解和回收利用的必需细胞机制细胞蛋白的杀死在亚微摩尔水平下杀死阴道链球菌。重要的是，抑制剂克服硝基药物抗药性，在毛刺感染的鼠模型中有效。我们也孤立了来自阴道和人类HeLa细胞的生化表征蛋白酶体，发现它们显示其肽底物特异性的显着差异，提供了设计新的有效和寄生虫选择性蛋白酶体抑制剂。基于这些有希望的发现，该项目具有总体目的是开发新型蛋白酶体抑制剂，其效力和选择性大大提高毛毛虫病。使用具有50倍选择性的命中化合物，我们将系统地发展阴道杆菌 - 特定的蛋白酶体抑制剂，使用药物化学努力的全面组合，功能通过多种临床菌株的阴道菌，寄生虫的生化和结构研究进行测试蛋白酶体以及鼠类感染模型中的功效和毒性测试。我们组装了一支精湛的团队寄生虫，蛋白酶生物学，抗菌药物方面的互补专业知识的研究人员发育以及药物和肽化学。团队有经验和记录临床前研究以建立蛋白酶体抑制剂作为治疗中的新类药物针对毛滴虫病的Armamentarium。