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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：
10367246
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/10367246
关键词：
Acute Adverse effects Appearance Benign Biochemical Biological Assay Biology Cell Line Cells Chemistry Cleaved cell 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 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 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 base cytotoxicity design drug candidate drug development effective therapy efficacy testing experience improved in vitro activity in vivo in vivo evaluation inhibitor/antagonist 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.

项目总结