Validation of the protein kinase Pf CLK3 as a multistage cross-species malarial drug target

Science. 2019 Aug 30;365(6456):eaau1682. doi: 10.1126/science.aau1682.

Abstract

The requirement for next-generation antimalarials to be both curative and transmission-blocking necessitates the identification of previously undiscovered druggable molecular pathways. We identified a selective inhibitor of the Plasmodium falciparum protein kinase PfCLK3, which we used in combination with chemogenetics to validate PfCLK3 as a drug target acting at multiple parasite life stages. Consistent with a role for PfCLK3 in RNA splicing, inhibition resulted in the down-regulation of more than 400 essential parasite genes. Inhibition of PfCLK3 mediated rapid killing of asexual liver- and blood-stage P. falciparum and blockade of gametocyte development, thereby preventing transmission, and also showed parasiticidal activity against P. berghei and P. knowlesi Hence, our data establish PfCLK3 as a target for drugs, with the potential to offer a cure-to be prophylactic and transmission blocking in malaria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / chemistry
  • Antimalarials / isolation & purification
  • Antimalarials / pharmacology*
  • Antimalarials / therapeutic use
  • Gametogenesis / drug effects
  • High-Throughput Screening Assays
  • Mice
  • Mice, Inbred BALB C
  • Molecular Targeted Therapy*
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Plasmodium falciparum / genetics
  • Protein Kinase Inhibitors / isolation & purification
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / genetics
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / genetics
  • RNA Splicing / genetics
  • Small Molecule Libraries / pharmacology

Substances

  • Antimalarials
  • Protein Kinase Inhibitors
  • Protozoan Proteins
  • Small Molecule Libraries
  • Clk dual-specificity kinases
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases