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TNP Analogues Inhibit the Virulence Promoting IP3-4 Kinase Arg1 in the Fungal Pathogen Cryptococcus neoformans

Biomolecules. 2022-10; 
Desmarini Desmarini, Daniel Truong, Lorna Wilkinson-White, Chandrika Desphande, Mario Torrado, Joel P Mackay, Jacqueline M Matthews, Tania C Sorrell, Sophie Lev, Philip E Thompson, Julianne Teresa Djordjevic
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摘要

New antifungals with unique modes of action are urgently needed to treat the increasing global burden of invasive fungal infections. The fungal inositol polyphosphate kinase (IPK) pathway, comprised of IPKs that convert IP3 to IP8, provides a promising new target due to its impact on multiple, critical cellular functions and, unlike in mammalian cells, its lack of redundancy. Nearly all IPKs in the fungal pathway are essential for virulence, with IP3-4 kinase (IP3-4K) the most critical. The dibenzylaminopurine compound, N2-(m-trifluorobenzylamino)-N6-(p-nitrobenzylamino)purine (TNP), is a commercially available inhibitor of mammalian IPKs. The ability of TNP to be adapted as an inhibitor of fungal IP3-4K has no... More

关键词

Cryptococcus neoformans; IP3-4K; TNP; antifungal drug discovery; dibenzylaminopurine; enzyme assay; fungal pathogens; inositol polyphosphate kinase; structure activity relationship; surface plasmon resonance.