Novel class of drug with superior potency against fungal IP3-4K and antifungal activity
Invasive fungal infections kill ~1.5 million people each year. Despite this, only a few antifungal drug classes are available which predominantly target the cell wall or the fungal sterol, ergosterol, and the most commonly used drugs are often poorly efficacious and/or toxic. Furthermore, drug-resistant strains are emerging. To address this unmet global health priority, we identified and characterized the fungal inositol polyphosphate kinase (IPK) pathway in the fungal priority pathogen Cryptococcus neoformans (WHO, 2022). We demonstrated that the IPK pathway is a promising novel antifungal drug target. It consists of a linear series of IPKs that convert IP3 to IP8. Nearly all IPKs are essential for fungal virulence, with Arg1, a IP3-4 kinase (IP3-4K) being the most crucial i.e., infection with an ARG1 deletion mutant in a mouse model is cleared by 3 days post-infection. We aim to develop inhibitors targeting fungal Arg1. Blocking IPK activity is therefore a novel antifungal therapeutic strategy but has not yet been validated chemically in pathogenic fungi. We previously showed that an ARG1 deletion mutant produces a sterilizing infection and have adapted the IP6K-selective compound, N2-(m-trifluorobenzylamino)-N6-(p-nitrobenzylamino)purine (TNP) to inhibit Arg1 from the priority pathogen C. neoformans. We have now further elaborated the TNP series to produce DT-23, which more potently inhibited purified CnArg, whilst retaining its selectivity over the human IPMK orthologue.