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

• 批准号: 8683888
• 负责人: RAYMOND C TRIEVEL
• 金额: $ 23.31万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8683888
• 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; Commit; 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; 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; 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; public health relevance; response; scaffold; screening; small molecule; tool

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)：烟曲霉是一种流行的真菌病原体，主要通过吸入孢子感染个人，然后孢子萌发并在整个肺部发送侵袭性菌丝延伸，导致临床支气管肺和侵袭性曲霉菌病。免疫受损的人，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征的人，以及患有囊性纤维化等慢性肺部疾病的人，患曲霉病的风险更高。此外, 患有真菌过敏症的人容易患上过敏性支气管肺曲霉菌病或真菌致敏的严重哮喘。目前的抗真菌疗法一般不适合治疗曲霉病，因为这些药物的毒性和副作用。这些缺点突显了临床上迫切需要开发新的抗真菌药物，以提供更好的疗效和更低的毒性。药物开发的目标之一是高柠檬酸合成酶(HCS)，这种酶催化真菌中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，这使得它成为抗真菌干预的一个有吸引力的靶点。此外，最近的研究表明，HCS对烟曲霉菌的支气管肺毒力是必不可少的，证实了该酶是抗真菌药物设计的新靶点。这项建议的总体目标是确定和表征高柠檬酸合成酶抑制剂，以阻止烟曲霉菌的生长。为此，我们提出了以下具体目标：1)通过体外高通量筛选鉴定烟曲霉菌小分子抑制剂；2)评价这些化合物对烟曲霉菌生长的抑制作用。我们预计，这些研究将为在细胞和动物模型中研究曲霉病提供化学探针，并为开发治疗由烟曲霉引起的一系列支气管肺部疾病的新疗法提供基础。