Development of Fungal-selective Molecules and Strategies to Target Hsp90

• Main Author: LeBlanc, Emmanuelle Victoria
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2020
• Subjects: Biochemistry; Genetics; Microbiology
• ISBN: 9798662392649

Invasive fungal infections have notoriously high mortality rates. A promising therapeutic strategy is to selectively target regulators of fungal stress responses, such as the essential molecular chaperone Hsp90, which enables virulence traits and antifungal drug resistance. The utility of current Hsp90 inhibitors as antifungals is limited by toxicity due to host chaperone inhibition. To address this challenge, my research aims to achieve fungal selectivity in targeting Hsp90 or its regulatory circuitry. I performed structure activity relationship analysis with >100 analogs of an Hsp90 inhibitor scaffold, which identified the first fully synthetic fungal-selective Hsp90 inhibitors. I also utilized chemogenomics to define the Hsp90 network in an important fungal pathogen, Cryptococcus neoformans, for which the circuitry through which Hsp90 regulates drug resistance and virulence remains enigmatic. I identified deletion mutants hypersensitive to Hsp90 inhibition, implicating genes that alter virulence traits, including fungal-specific components, providing an expanded set of targets for therapeutic intervention.