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. 项目概要。 在过去五年中，球孢子菌病（谷热）的发病率一直在以 惊人的发病率，使其成为美国社区获得性肺炎的常见原因。尽管 很大程度上诊断不足，目前中度至重度病例的治疗涉及应用 两性霉素B或唑类抗真菌药如氟康唑，两种药物的适应症并发严重 副作用和药物相互作用。如果没有其他选择，患者往往得不到治疗并且病情很差 临床预后。由于许多线索被确定为战斗，这一事实使情况变得更加复杂 迄今为止，球孢子菌病目标已确定抗真菌目标，但未考虑其功效 针对真菌宿主中的这些途径。在过去的十年里，我们的团队专注于开发 人类剪接的小分子调节剂。我们已经了解了系统之间独特的相互作用是如何- 广泛且基于机制的理解在开发可行的治疗线索方面发挥着关键作用 致癌疾病。该项目探索翻译剪接调节剂作为下一代治疗方法 通过将药物化学优化工作与基因和转录组范围的工具相结合来治疗球孢子菌病。 这个高风险/高回报的项目将化学生物学与药物化学的活跃项目结合起来 评估、测试和验证用于治疗严重疾病的剪接体靶向小分子 球孢子菌病。