Inhibition of resistance-refractory P. falciparum kinase PKG delivers prophylactic, blood stage, and transmission-blocking antiplasmodial activity

Vanaerschot, M. et al. (2020) Inhibition of resistance-refractory P. falciparum kinase PKG delivers prophylactic, blood stage, and transmission-blocking antiplasmodial activity. Cell Chemical Biology, 27(7), 806-816.e8. (doi: 10.1016/j.chembiol.2020.04.001) (PMID:32359426) (PMCID:PMC7369637)

Abstract

The search for antimalarial chemotypes with modes of action unrelated to existing drugs has intensified with the recent failure of first-line therapies across Southeast Asia. Here, we show that the trisubstituted imidazole MMV030084 potently inhibits hepatocyte invasion by Plasmodium sporozoites, merozoite egress from asexual blood stage schizonts, and male gamete exflagellation. Metabolomic, phosphoproteomic, and chemoproteomic studies, validated with conditional knockdown parasites, molecular docking, and recombinant kinase assays, identified cGMP-dependent protein kinase (PKG) as the primary target of MMV030084. PKG is known to play essential roles in Plasmodium invasion of and egress from host cells, matching MMV030084's activity profile. Resistance selections and gene editing identified tyrosine kinase-like protein 3 as a low-level resistance mediator for PKG inhibitors, while PKG itself never mutated under pressure. These studies highlight PKG as a resistance-refractory antimalarial target throughout the Plasmodium life cycle and promote MMV030084 as a promising Plasmodium PKG-targeting chemotype.

• Item Type: Articles
• Additional Information: This work was supported by the Bill and Melinda Gates Foundation that funds the Malarial Drug Accelerator (MalDA) consortium (OPP1054480 to E.A.W., D.A.F., M.C.S.L., and M.L., and OPP1162467 to J.C.N.), the Medicines for Malaria Venture (08/0015 to D.A.F.), the NIH (R01 AI090141 to E.A.W.) the Italian Ministries of Health and Foreign Affairs (ISARP2018-ISS to P.A.), and the LSHTM/Wellcome ISSF (to M.D.). K.C. gratefully acknowledges the support of the University of Cape Town, the South African Medical Research Council, the South African Research Chairs Initiative of the Department of Science and Innovation administered through the South African National Research Foundation, and the Global Challenges Research Fund (Synchrotron Techniques for African Research and Technology project). S.M. was supported by a Human Frontier Science Program long-term fellowship award.
• Keywords: Plasmodium falciparum, cGMP-dependent protein kinase (PKG), chemoproteomics, conditional knockdown, kinase, malaria drug discovery, phosphoproteomics, resistance, target identification.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Dwomoh, Dr Louis and Tobin, Andrew
• Authors: Vanaerschot, M., Murithi, J. M., Pasaje, C. F. A., Ghidelli-Disse, S., Dwomoh, L., Bird, M., Spottiswoode, N., Mittal, N., Arendse, L. B., Owen, E. S., Wicht, K. J., Siciliano, G., Bösche, M., Yeo, T., Kumar, T. R. S., Mok, S., Carpenter, E. F., Giddins, M. J., Sanz, O., Ottilie, S., Alano, P., Chibale, K., Llinás, M., Uhlemann, A.-C., Delves, M., Tobin, A. B., Doerig, C., Winzeler, E. A., Lee, M. C. S., Niles, J. C., and Fidock, D. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Cell Chemical Biology
• Publisher: Elsevier (Cell Press)
• ISSN: 2451-9456
• ISSN (Online): 2451-9448
• Published Online: 30 April 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Cell Chemical Biology 27(7): 806-816.e8
• Publisher Policy: Reproduced under a Creative Commons License