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.