Discovery of Thymidylate Kinase Inhibitors for Anti-Fungal Applications

发现用于抗真菌应用的胸苷酸激酶抑制剂

• 批准号: 10553160
• 负责人: GORDON S. RULE
• 金额: $ 23.53万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-18 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553160
• 关键词: Affinity; Antifungal Agents; Antifungal Therapy; Azoles; Binding; Biological Assay; Biology; Candida; Candida albicans; Candida auris; Candidiasis; Catheters; Chemicals; Clinical; DNA Repair; DNA biosynthesis; DNA metabolism; Dangerousness; Darkness; Data; Development; Diphosphates; Diversity Library; Docking; Drug Evaluation; Drug resistance; Enzymatic Biochemistry; Enzyme Stability; Enzymes; Evaluation; Feedback; Fluconazole; Fluorescence; Goals; Growth; Human; Human Cell Line; Immunocompromised Host; Implant; Infection; Lead; Libraries; Ligands; Location; Machine Learning; Measures; Medical; Methods; Microbial Biofilms; Minimum Inhibitory Concentration measurement; Mycoses; Nuclear Magnetic Resonance; Nucleotides; Oranges; Pharmaceutical Preparations; Phosphorylation; Population; Production; Property; Proteins; Quantitative Structure-Activity Relationship; Reproducibility; Research Project Grants; Signal Transduction; Site; Specificity; Structure; Structure-Activity Relationship; Testing; Thymidine Monophosphate; Time; Toxic effect; X-Ray Crystallography; analog; candidate identification; candidate selection; computational chemistry; computerized tools; drug discovery; functional group; high throughput screening; inhibitor; kinase inhibitor; medical implant; mortality; novel; pathogen; pathogenic fungus; protein protein interaction; resistant strain; screening; small molecule inhibitor; small molecule libraries; thymidylate kinase; virtual screening; yeast genetics

Discovery of Thymidylate Kinase Inhibitors for Anti-Fungal Applications Abstract: Infections due to the fungal pathogen Candida albicans are devastating to the human population. C. albicans causes over 40,000 cases of invasive candidiasis/year in the US alone, with an estimated mortality rate of approximately 20%. There are only a small number of approved anti-fungal agents and resistance to these drugs is becoming common. We propose to isolate and characterize inhibitors of thymidylate kinase that can be developed as anti-fungal drugs. Thymidylate kinase catalyzes the phosphorylation of thymidine monophosphate to diphosphate, and it is an essential step in the production of TTP, which is required for DNA replication and repair. We propose to use high-throughput screening (HTS) of compound libraries, computational drug discovery, and Nuclear magnetic resonance (NMR) based screening of fragment libraries, to identify lead compounds. The proposal leverages expertise in thymidylate kinase enzymology and NMR (Rule), HTS (Johnston), computational chemistry (Isayev), and C. albicans biology (Mitchell).

胸腺嘧啶酸激酶抑制剂在抗真菌应用中的发现 摘要： 由真菌病原体白色念珠菌引起的感染对人类人口是毁灭性的。C。 白念珠菌每年仅在美国就导致超过4万例侵袭性念珠菌病，估计死亡人数 利率约为20%。只有少数获得批准的抗真菌药物和抗药性 这些药物正变得越来越普遍。我们建议分离和鉴定胸苷酸激酶的抑制剂。 它可以被开发为抗真菌药物。胸苷激酶催化胸腺嘧啶核苷磷酸化 一磷酸转化为二磷酸，是生产TTP的关键步骤，TTP是生产TTP所需的 DNA复制和修复。我们建议使用化合物文库的高通量筛选(HTS)， 计算机药物发现和基于核磁共振的片段筛选 文库，以识别先导化合物。该提案充分利用了胸苷酸激酶酶学方面的专业知识 和核磁共振(规则)、高温超导(约翰斯顿)、计算化学(伊萨耶夫)和白色念珠菌生物学(米切尔)。