Splice modulatory therapy for valley fever

谷热的剪接调节疗法

基本信息

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
项目类别：
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

项目摘要

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，患者往往无法得到治疗，并且状况不佳临床预后。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。该计划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。