Splice modulatory therapy for valley fever

谷热的剪接调节疗法

• 批准号: 10042570
• 负责人: Michael D. Burkart
• 金额: $ 23.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042570
• 关键词: Acute Myelocytic Leukemia; Amphotericin B; Antifungal Agents; Arizona; Azoles; Biological; Biological Markers; Biology; California; Cells; Chemicals; Clinical; Coccidioides immitis; Coccidioides posadasii; Coccidioidomycosis; Communities; Development; Diagnosis; Disease; Drug Interactions; Dust; Evaluation; Event; Family; Fluconazole; Funding; Future; Genes; Goals; Human; Incidence; Individual; Infection; Investigation; Laboratories; Lead; Left; Life; Messenger RNA; Modernization; Natural Products; Oncogenic; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Pneumonia; Positioning Attribute; Precipitation; Preparation; RNA Splicing; Reporting; Seasons; Series; Side; Spliceosomes; Structure; System; Systems Biology; Techniques; Testing; Therapeutic; Translating; Translations; United States; Work; analog; anti-cancer; base; cancer cell; combat; desert fever; design; flu; fungus; high reward; high risk; new therapeutic target; next generation; novel; outcome forecast; preclinical study; programs; scaffold; side effect; small molecule; therapeutic target; tool; transcriptome; transcriptomics

7. Project Summary. Over the last five years, the incidence of coccidioidomycosis (Valley Fever) has been increasing at a remarkable rate, making it a common cause of community-acquired pneumonia in the United States. While largely under-diagnosed, the treatment of moderate to severe cases currently involves application of amphotericin B or azole antifungals such as fluconazole, two drugs with indications complicated by severe side-effects and drug interactions. Without other options, patients are often left untreated and with a poor clinical prognosis. This is further complicated by the fact that many of the leads identified to combat coccidioidomycosis to date target established antifungal targets, without consideration of the efficacy of targeting these pathways in their fungal hosts. Over the last decade, our team has focused on the development of small molecule modulators of human splicing. We have learned how the unique interplay between systems- wide and mechanism-based understanding plays a key role in developing viable therapeutic leads for oncogenic diseases. This program explores the translation splice modulators as next-generation treatments for coccidioidomycosis by uniting medicinal chemical optimization efforts with gene and transcriptome-wide tools. This high-risk / high-reward program unites chemical biology with an active program in medicinal chemistry to evaluate, test and validate the spliceosome-targeting small molecules for the treatment of severe coccidioidomycosis.

7。项目摘要。 在过去的五年中，球虫菌病（山谷热）的发生率一直在增加 显着的速度，使其成为美国获得社区获得性肺炎的普遍原因。尽管 在很大程度上未被诊断出来，当前对中度至重度病例的治疗涉及应用 两性霉素B或偶氮抗真菌性抗真菌剂，例如氟康唑，两种药物具有严重的适应症。 副作用和药物相互作用。没有其他选择，患者通常不受治疗，并且差 临床预后。这一事实使许多铅被确定为战斗，这更加复杂 球虫菌病至今已建立的抗真菌靶标，而无需考虑 针对其真菌宿主中的这些途径。在过去的十年中，我们的团队专注于发展 人类剪接的小分子调节剂。我们已经了解了系统之间的独特相互作用 - 基于机制的广泛理解在开发可行的治疗铅方面起着关键作用 致癌性疾病。该程序探讨了翻译剪接调制器作为下一代处理 球霉菌病通过将药物化学优化工作与基因和全转录组的工具结合在一起。 这个高风险 /高回报计划将化学生物学与药物化学中的活跃程序团结起来 评估，测试和验证针对剪接体的小分子以治疗严重 球菌病。