Inhibition of Resistance-Refractory P. falciparum Kinase PKG Delivers Prophylactic, Blood Stage, and Transmission-Blocking Antiplasmodial Activity

Manu Vanaerschot, James M. Murithi, Charisse Flerida A. Pasaje, Sonja Ghidelli-Disse, Louis Dwomoh, Megan Bird, Natasha Spottiswoode, Nimisha Mittal, Lauren B. Arendse, Edward S. Owen, Kathryn J. Wicht, Giulia Siciliano, Markus Bösche, Tomas Yeo, T. R.Santha Kumar, Sachel Mok, Emma F. Carpenter, Marla J. Giddins, Olalla Sanz, Sabine OttiliePietro Alano, Kelly Chibale, Manuel Llinás, Anne Catrin Uhlemann, Michael Delves, Andrew B. Tobin, Christian Doerig, Elizabeth A. Winzeler, Marcus C.S. Lee, Jacquin C. Niles, David A. Fidock

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)806-816.e8
JournalCell Chemical Biology
Volume27
Issue number7
DOIs
StatePublished - Jul 16 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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