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Inositol Polyphosphate Kinases, Fungal Virulence and Drug Discovery

Li, C; Lev, S; Saiardi, A; Desmarini, D; Sorrell, TC; Djordjevic, JT; (2016) Inositol Polyphosphate Kinases, Fungal Virulence and Drug Discovery. Journal of Fungi , 2 (3) , Article 24. 10.3390/jof2030024. Green open access

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Abstract

Opportunistic fungi are a major cause of morbidity and mortality world-wide, particularly in immunocompromised individuals. Developing new treatments to combat invasive fungal disease is challenging given that fungal and mammalian host cells are eukaryotic, with similar organization and physiology. Even therapies targeting unique fungal cell features have limitations and drug resistance is emerging. New approaches to the development of antifungal drugs are therefore needed urgently. Cryptococcus neoformans, the commonest cause of fungal meningitis worldwide, is an accepted model for studying fungal pathogenicity and driving drug discovery. We recently characterized a phospholipase C (Plc1)-dependent pathway in C. neoformans comprising of sequentially-acting inositol polyphosphate kinases (IPK), which are involved in synthesizing inositol polyphosphates (IP). We also showed that the pathway is essential for fungal cellular function and pathogenicity. The IP products of the pathway are structurally diverse, each consisting of an inositol ring, with phosphate (P) and pyrophosphate (PP) groups covalently attached at different positions. This review focuses on (1) the characterization of the Plc1/IPK pathway in C. neoformans; (2) the identification of PP-IP₅ (IP₇) as the most crucial IP species for fungal fitness and virulence in a mouse model of fungal infection; and (3) why IPK enzymes represent suitable candidates for drug development.

Type: Article
Title: Inositol Polyphosphate Kinases, Fungal Virulence and Drug Discovery
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.3390/jof2030024
Publisher version: http://doi.org/10.3390/jof2030024
Language: English
Additional information: Copyright © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
Keywords: antifungal compounds; Cryptococcus neoformans; inositol polyphosphate kinases; inositol pyrophosphates; PP-IP5; fungal virulence; cryptococcal meningitis; drug discovery
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10053218
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