{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T17:50:56Z","timestamp":1785520256994,"version":"3.56.0"},"reference-count":52,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T00:00:00Z","timestamp":1666224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Sydney Drug Discovery Institute","award":["APP1183939"],"award-info":[{"award-number":["APP1183939"]}]},{"name":"University of Sydney Drug Discovery Institute","award":["APP1058779"],"award-info":[{"award-number":["APP1058779"]}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council (NHMRC) of Australia","doi-asserted-by":"publisher","award":["APP1183939"],"award-info":[{"award-number":["APP1183939"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council (NHMRC) of Australia","doi-asserted-by":"publisher","award":["APP1058779"],"award-info":[{"award-number":["APP1058779"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Australian Government","award":["APP1183939"],"award-info":[{"award-number":["APP1183939"]}]},{"name":"Australian Government","award":["APP1058779"],"award-info":[{"award-number":["APP1058779"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>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 not been investigated. We purified IP3-4K from the human pathogens, Cryptococcus neoformans and Candida albicans, and optimised enzyme and surface plasmon resonance (SPR) assays to determine the half inhibitory concentration (IC50) and binding affinity (KD), respectively, of TNP and 38 analogues. A novel chemical route was developed to efficiently prepare TNP analogues. TNP and its analogues demonstrated inhibition of recombinant IP3-4K from C. neoformans (CnArg1) at low \u00b5M IC50s, but not IP3-4K from C. albicans (CaIpk2) and many analogues exhibited selectivity for CnArg1 over the human equivalent, HsIPMK. Our results provide a foundation for improving potency and selectivity of the TNP series for fungal IP3-4K.<\/jats:p>","DOI":"10.3390\/biom12101526","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T20:35:55Z","timestamp":1666298155000},"page":"1526","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["TNP Analogues Inhibit the Virulence Promoting IP3-4 Kinase Arg1 in the Fungal Pathogen Cryptococcus neoformans"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9322-3198","authenticated-orcid":false,"given":"Desmarini","family":"Desmarini","sequence":"first","affiliation":[{"name":"Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, Westmead, NSW 2145, Australia"},{"name":"Sydney Institute for Infectious Diseases, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7188-606X","authenticated-orcid":false,"given":"Daniel","family":"Truong","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorna","family":"Wilkinson-White","sequence":"additional","affiliation":[{"name":"Sydney Analytical, Core Research Facilities, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrika","family":"Desphande","sequence":"additional","affiliation":[{"name":"Sydney Analytical, Core Research Facilities, The University of Sydney, Sydney, NSW 2006, Australia"},{"name":"School of Life & Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Torrado","sequence":"additional","affiliation":[{"name":"Sydney Analytical, Core Research Facilities, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7508-8033","authenticated-orcid":false,"given":"Joel P.","family":"Mackay","sequence":"additional","affiliation":[{"name":"School of Life & Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline M.","family":"Matthews","sequence":"additional","affiliation":[{"name":"School of Life & Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9460-0960","authenticated-orcid":false,"given":"Tania C.","family":"Sorrell","sequence":"additional","affiliation":[{"name":"Sydney Institute for Infectious Diseases, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3511-457X","authenticated-orcid":false,"given":"Sophie","family":"Lev","sequence":"additional","affiliation":[{"name":"Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, Westmead, NSW 2145, Australia"},{"name":"Sydney Institute for Infectious Diseases, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5910-7625","authenticated-orcid":false,"given":"Philip E.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4207-4115","authenticated-orcid":false,"given":"Julianne Teresa","family":"Djordjevic","sequence":"additional","affiliation":[{"name":"Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, Westmead, NSW 2145, Australia"},{"name":"Sydney Institute for Infectious Diseases, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia"},{"name":"Western Sydney Local Health District, Westmead, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bongomin, F., Gago, S., Oladele, R.O., and Denning, D.W. 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