Development of a Novel Class of Antifungal Therapy

Development of a Novel Class of Antifungal Therapy: This project aims to address the urgent need for new antifungal treatments by developing a novel class of small molecules with potent activity against drug-resistant fungal strains. Using proprietary chemical structures, SHY Therapeutics will identify and optimize compounds for clinical use, focusing on efficacy, safety, and overcoming current treatment limitations. Fungal infections affect millions of people each year, posing a significant global health burden. Existing antifungal therapies are often inadequate due to drug resistance, toxicity, and insufficient efficacy, particularly in immunocompromised populations. To tackle this challenge, SHY Therapeutics has developed a wide range of new and proprietary chemical structures, with preliminary screening identifying novel compounds active against Cryptococcus neoformans, Candida auris, Candida albicans, and Candida parapsilosis. In this Phase 1 proposal, we aim to identify novel classes of small molecules to be optimized for anti-fungal therapy through 3 aims: Aim 1 of this project is to use a Structure-Activity Relationship (SAR) approach to optimize anti-fungal activity of newly synthesized compounds, focusing on Candida auris and Cryptococcus neoformans. The most active compounds will undergo further testing against a panel of over 50 fungal strains, including drug-resistant variants, and will be evaluated for ADME/PK properties and in vivo efficacy in murine infection models. Aim 2 focuses on identifying the protein targets interacting with and inhibited by the identified small molecules using Drug Affinity Responsive Target Stability (DARTS), followed by development of cell-free assays to gain insights into the mechanism of action of the identified small molecules. Aim 3 involves conducting a proof of concept in vivo efficacy study in a murine disseminated candidiasis model, prioritizing a promising hit compound, SHY-4. SHY has a successful track record in the design, synthesis and testing of novel compounds in other therapeutic areas, resulting in 10 issued patents to date. SHY Therapeutics has already identified compounds with strong antifungal activity and minimal impact on mammalian cell viability, suggesting a potentially superior safety profile compared to current FDA-approved drugs.