A specific inhibitor of PfCDPK4 blocks malaria transmission: chemical-genetic validation

J Infect Dis. 2014 Jan 15;209(2):275-84. doi: 10.1093/infdis/jit522. Epub 2013 Oct 10.

Abstract

Malaria parasites are transmitted by mosquitoes, and blocking parasite transmission is critical in reducing or eliminating malaria in endemic regions. Here, we report the pharmacological characterization of a new class of malaria transmission-blocking compounds that acts via the inhibition of Plasmodia CDPK4 enzyme. We demonstrate that these compounds achieved selectivity over mammalian kinases by capitalizing on a small serine gatekeeper residue in the active site of the Plasmodium CDPK4 enzyme. To directly confirm the mechanism of action of these compounds, we generated P. falciparum parasites that express a drug-resistant methionine gatekeeper (S147 M) CDPK4 mutant. Mutant parasites showed a shift in exflagellation EC50 relative to the wild-type strains in the presence of compound 1294, providing chemical-genetic evidence that CDPK4 is the target of the compound. Pharmacokinetic analyses suggest that coformulation of this transmission-blocking agent with asexual stage antimalarials such as artemisinin combination therapy (ACT) is a promising option for drug delivery that may reduce transmission of malaria including drug-resistant strains. Ongoing studies include refining the compounds to improve efficacy and toxicological properties for efficient blocking of malaria transmission.

Keywords: Plasmodium falciparum; bumped kinase inhibitors; calcium-dependent protein kinase 4; malaria transmission-blocking.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antimalarials / isolation & purification
  • Antimalarials / metabolism*
  • Antimalarials / pharmacokinetics
  • Enzyme Inhibitors / isolation & purification
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / pharmacokinetics
  • Flagella / drug effects
  • Flagella / physiology
  • Mice
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / physiology
  • Protein Kinases / metabolism*
  • Protozoan Proteins / antagonists & inhibitors*

Substances

  • Antimalarials
  • Enzyme Inhibitors
  • Protozoan Proteins
  • Protein Kinases
  • calcium-dependent protein kinase