Discovery of Thymidylate Kinase Inhibitors for Anti-Fungal Applications

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Discovery of Thymidylate Kinase Inhibitors for Anti-Fungal Applications Abstract: Infections due to the fungal pathogen Candida albicans are devastating to the human population. C. albicans causes over 40,000 cases of invasive candidiasis/year in the US alone, with an estimated mortality rate of approximately 20%. There are only a small number of approved anti-fungal agents and resistance to these drugs is becoming common. We propose to isolate and characterize inhibitors of thymidylate kinase that can be developed as anti-fungal drugs. Thymidylate kinase catalyzes the phosphorylation of thymidine monophosphate to diphosphate, and it is an essential step in the production of TTP, which is required for DNA replication and repair. We propose to use high-throughput screening (HTS) of compound libraries, computational drug discovery, and Nuclear magnetic resonance (NMR) based screening of fragment libraries, to identify lead compounds. The proposal leverages expertise in thymidylate kinase enzymology and NMR (Rule), HTS (Johnston), computational chemistry (Isayev), and C. albicans biology (Mitchell).