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

Desmarini Desmarini1,2, Daniel Truong3, Lorna Wilkinson-White4

  • 1Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, Westmead, NSW 2145, Australia.

Biomolecules
|October 27, 2022
PubMed
Summary

New antifungals are crucial for invasive fungal infections. Researchers investigated TNP analogues as inhibitors of fungal inositol polyphosphate kinase 3-4 (IPK3-4), finding selective inhibition in Cryptococcus neoformans.

Keywords:
Cryptococcus neoformansIP3-4KTNPantifungal drug discoverydibenzylaminopurineenzyme assayfungal pathogensinositol polyphosphate kinasestructure activity relationshipsurface plasmon resonance

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Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Mycology

Background:

  • Invasive fungal infections pose a growing global health threat, necessitating novel antifungal agents.
  • The fungal inositol polyphosphate kinase (IPK) pathway is a promising antifungal target due to its essential role in virulence and lack of redundancy.
  • IP3-4 kinase (IP3-4K) is the most critical enzyme in this pathway.

Purpose of the Study:

  • To investigate the potential of the mammalian IPK inhibitor TNP and its analogues as inhibitors of fungal IP3-4K.
  • To develop and optimize assays for evaluating TNP analogues against fungal IP3-4K.
  • To assess the potency and selectivity of TNP analogues for fungal IP3-4K over human orthologs.

Main Methods:

  • Purification of IP3-4K from *Cryptococcus neoformans* and *Candida albicans*.
  • Optimization of enzyme and surface plasmon resonance (SPR) assays.
  • Determination of half inhibitory concentration (IC50) and binding affinity (KD) for TNP and 38 analogues.
  • Synthesis of novel TNP analogues via a new chemical route.

Main Results:

  • TNP and its analogues inhibited recombinant *C. neoformans* IP3-4K (CnArg1) with low µM IC50 values.
  • Inhibition was not observed for *C. albicans* IP3-4K (Caiplk2).
  • Several analogues demonstrated selectivity for fungal CnArg1 over the human ortholog (HsIPMK).

Conclusions:

  • The TNP series shows potential as a starting point for developing selective inhibitors of fungal IP3-4K.
  • Further optimization of TNP analogues could lead to new antifungal therapies targeting critical fungal pathways.