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（由申请方提供）：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体，孢子随后发芽并在整个肺部传播侵入性菌丝延伸，导致临床支气管肺炎和侵袭性曲霉病。免疫功能低下的个体，如烧伤患者、移植受者、接受化疗的癌症患者和患有HIV/AIDS或其他免疫缺陷综合征的个体，以及患有慢性肺病如囊性纤维化的个体，表现出更高的发生曲霉病的风险。此外，本发明还提供了一种方法， 具有真菌超敏性的个体易于发展为过敏性支气管肺曲霉病或具有真菌致敏性的严重哮喘。目前的抗真菌治疗通常不适合曲霉病的治疗，由于这些药物的毒性和副作用。这些缺点强调了临床迫切需要开发新的抗真菌药物，提供更大的疗效和更低的毒性。药物开发的一个目标是高柠檬酸合酶（HCS），这种酶催化真菌中赖氨酸生物合成的第一个关键步骤。HCS在A.烟曲霉，但在人类中不存在，使其成为抗真菌干预的有吸引力的目标。此外，最近的研究表明，HCS是必不可少的支气管肺毒力的A。烟曲霉，验证这种酶作为抗真菌药物设计的新目标。本提案的总体目标是鉴定和表征阻断A.烟熏。为此，我们提出了以下具体目标：1）鉴定A.通过体外高通量筛选评估这些化合物在抑制烟曲霉HCS中的功效，以及2）评估这些化合物在抑制烟曲霉HCS中的功效。烟曲霉生长我们设想，这些研究将产生化学探针，用于研究曲霉菌病的细胞为基础的动物模型，并提供了一个基础，为开发新的治疗方法，用于治疗支气管肺疾病的频谱由A。烟熏。