Homocitrate Synthase Inhibitors as Novel Antifungal Agents for Aspergillus

高柠檬酸合酶抑制剂作为曲霉菌的新型抗真菌剂

基本信息

批准号：
8916542
负责人：
RAYMOND C TRIEVEL
金额：
$ 19.38万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8916542
关键词：
AIDS/HIV problem Acetyl Coenzyme A Adverse effects Allergic Bronchopulmonary Aspergillosis Animal Model Animals Antifungal Agents Antifungal Therapy Aspergillosis Aspergillus Aspergillus fumigatus Asthma Biological Assay Biological Availability Biological Models Breathing Burn injury Cancer Patient Cells Chemicals Chronic Chronic lung disease Clinical Collection Contracts Cystic Fibrosis Databases Development Disease Dose Drug Design Drug resistance Effectiveness Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Exhibits Future Genomics Germination Goals Growth HIV Health Homocitrate synthase Human Hypersensitivity Immunocompromised Host Immunologic Deficiency Syndromes In Vitro Individual Infection Intervention Laboratories Lead Libraries Lung Lysine Lysine Biosynthesis Pathway Metabolic Michigan Morbidity - disease rate Mycoses Patients Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phase Powder dose form Probability Publishing Reporting Reproduction spores Resources Risk Structure Testing Toxic effect Transplant Recipients Universities Virulence alpha ketoglutarate analog asthmatic base chemotherapy combat cytotoxicity density design drug development fungus high throughput screening improved in vivo inhibitor/antagonist mimetics mortality mouse model novel novel therapeutics pathogen preference response scaffold screening small molecule tool

项目摘要

DESCRIPTION (provided by applicant): Aspergillus fumigatus is a prevalent fungal pathogen that primarily infects individuals through inhalation of spores that subsequently germinate and send invasive hyphal extensions throughout the lungs, resulting in clinical bronchopulmonary and invasive aspergillosis. Individuals who are immunocompromised, such as burn patients, transplant recipients, cancer patients undergoing chemotherapy, and individuals suffering from HIV/AIDS or other immunodeficiency syndromes, as well as those suffering from chronic lung disease, such as cystic fibrosis, exhibit a higher risker of developing aspergillosis. In addition, individuals with fungal hypersensitivity are susceptible to developing allergic bronchopulmonary aspergillosis or severe asthma with fungal sensitization. Current antifungal therapies are generally unsuitable for the treatment of aspergillosis due to the toxicity and side effects associated with these drugs. These shortcomings underscore an urgent clinical need to develop new antifungal drugs that offer greater efficacy and a lower toxicity profile. One such target for drug development is homocitrate synthase (HCS), the enzyme that catalyzes the first and committed step in lysine biosynthesis in fungi. HCS is conserved in A. fumigatus, but is absent in humans, rendering it an attractive target for antifungal intervention. Further, recent studies have demonstrated that HCS is essential to the bronchopulmonary virulence of A. fumigatus, validating this enzyme as a novel target for antifungal drug design. The overall objective of this proposal is to identify and characterize homocitrate synthase inhibitors that block the growth of A. fumigatus. Toward this objective, we propose the following specific aims: 1) to identify of small molecule inhibitors of A. fumigatus HCS by in vitro high-throughput screening and 2) to assess the efficacy of these compounds in inhibiting A. fumigatus growth. We envision that these studies will yield chemical probes for studying aspergillosis in cell-based and animal models and provide a basis for developing new therapeutics for treating a spectrum of bronchopulmonary diseases caused by A. fumigatus.

描述（由申请人提供）：烟曲霉是一种常见的真菌病原体，主要通过吸入孢子来感染个体，孢子随后发芽并将侵入性菌丝延伸到整个肺部，导致临床支气管肺和侵袭性曲霉病。免疫功能低下的个体，例如烧伤患者、移植受者、接受化疗的癌症患者、患有艾滋病毒/艾滋病或其他免疫缺陷综合症的个体，以及患有慢性肺病（例如囊性纤维化）的个体，表现出较高的患肺病的风险。发展为曲霉病。此外，患有真菌过敏的个体容易患上过敏性支气管肺曲霉病或伴有真菌过敏的严重哮喘。由于与这些药物相关的毒性和副作用，目前的抗真菌疗法通常不适合治疗曲霉菌病。这些缺点凸显了临床迫切需要开发具有更高功效和更低毒性的新型抗真菌药物。药物开发的一个这样的目标是高柠檬酸合酶（HCS），这种酶催化真菌赖氨酸生物合成的第一步和关键步骤。 HCS 在烟曲霉中是保守的，但在人类中不存在，这使其成为抗真菌干预的一个有吸引力的目标。此外，最近的研究表明，HCS 对于烟曲霉的支气管肺毒力至关重要，验证了这种酶作为抗真菌药物设计的新靶点。该提案的总体目标是鉴定和表征阻止烟曲霉生长的高柠檬酸合酶抑制剂。为了实现这一目标，我们提出以下具体目标：1) 通过体外高通量筛选鉴定烟曲霉 HCS 的小分子抑制剂，2) 评估这些化合物抑制烟曲霉生长的功效。我们预计这些研究将产生用于在细胞和动物模型中研究曲霉病的化学探针，并为开发治疗由烟曲霉引起的一系列支气管肺疾病的新疗法提供基础。