Parasite and host kinases as targets for antimalarials

Ong, H. W., Adderley, J., Tobin, A. B. , Drewry, D. H. and Doerig, C. (2023) Parasite and host kinases as targets for antimalarials. Expert Opinion on Therapeutic Targets, 27(2), pp. 151-169. (doi: 10.1080/14728222.2023.2185511) (PMID:36942408)

Abstract

Introduction: The deployment of Artemisinin-based combination therapies and transmission control measures led to a decrease in the global malaria burden over the recent decades. Unfortunately, this trend is now reversing, in part due to resistance against available treatments, calling for the development of new drugs against untapped targets to prevent cross-resistance. Areas covered: In view of their demonstrated druggability in noninfectious diseases, protein kinases represent attractive targets. Kinase-focussed antimalarial drug discovery is facilitated by the availability of kinase-targeting scaffolds and large libraries of inhibitors, as well as high-throughput phenotypic and biochemical assays. We present an overview of validated Plasmodium kinase targets and their inhibitors, and briefly discuss the potential of host cell kinases as targets for host-directed therapy. Expert opinion: We propose priority research areas, including (i) diversification of Plasmodium kinase targets (at present most efforts focus on a very small number of targets); (ii) polypharmacology as an avenue to limit resistance (kinase inhibitors are highly suitable in this respect); and (iii) preemptive limitation of resistance through host-directed therapy (targeting host cell kinases that are required for parasite survival) and transmission-blocking through targeting sexual stage-specific kinases as a strategy to protect curative drugs from the spread of resistance.

• Item Type: Articles
• Additional Information: This manuscript was funded by RMIT University and grants from the Australian National Health and Medical Research Council to Anonymized and Anonymized (APP2003712) and a grant from the Victorian Government Medical Research Acceleration Fund (Round 4). Work in the laboratory of D.H. Drewry is supported by National Institutes of Health under grant no. 1R44AI150237-01. The laboratory of D.H. Drewry is grateful for the support by the Structural Genomics Consortium (SGC), a registered charity (no. 1097737) that receives funds from Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/KTH/ Diamond Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN grant 875510], Janssen, Merck KGaA (aka EMD in Canada and USA), Pfizer, and Takeda.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Tobin, Andrew
• Authors: Ong, H. W., Adderley, J., Tobin, A. B., Drewry, D. H., and Doerig, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Research Centre: Mazumdar-Shaw Advanced Research Centre (ARC) > Technologies Touching Life
• Journal Name: Expert Opinion on Therapeutic Targets
• Publisher: Taylor & Francis
• ISSN: 1472-8222
• ISSN (Online): 1744-7631
• Published Online: 20 March 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Expert Opinion on Therapeutic Targets 27(2): 151-169
• Publisher Policy: Reproduced under a Creative Commons License