Splice modulatory therapy for valley fever

7.项目总结。 在过去的五年中，球孢子菌病(谷热)的发病率一直在以 这使其成为美国社区获得性肺炎的常见原因。而当 在很大程度上诊断不足，中到重度病例的治疗目前涉及到应用 两性霉素B或唑类抗真菌药，如氟康唑，两种有适应症的药物合并重症 副作用和药物相互作用。在没有其他选择的情况下，患者往往得不到治疗，生活质量很差。 临床预后。这一点变得更加复杂，因为许多被确定为打击的线索 球孢子菌病迄今已建立抗真菌靶点，未考虑其疗效 以真菌宿主中的这些通路为靶点。在过去的十年里，我们的团队一直专注于 人类剪接的小分子调节剂。我们已经了解到系统之间的独特相互作用- 广泛和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 致癌性疾病。该计划探索翻译剪接调节器作为下一代治疗 通过将药物化学优化努力与基因和转录组工具相结合来治疗球孢子菌病。 这一高风险/高回报的计划将化学生物学与药物化学的积极计划结合起来，以 剪接体靶向小分子治疗重型肝炎的评价、测试和验证 球孢子菌病。

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.