Potential Role of Plasmodium Falciparum Exported Protein 1 in the Chloroquine Mode of Action

Int J Parasitol Drugs Drug Resist. 2018 Apr;8(1):31-35. doi: 10.1016/j.ijpddr.2017.12.003. Epub 2017 Dec 27.

Abstract

In the human malaria parasite Plasmodium falciparum, membrane glutathione S-transferases (GST) have recently emerged as potential cellular detoxifying units and as drug target candidates with the artemisinin (ART) class of antimalarials inhibiting their activity at single-digit nanomolar potency when activated by iron sources such as cytotoxic hematin. Here we put forward the hypothesis that the membrane GST Plasmodium falciparum exported protein 1 (PfEXP1, PF3D7_1121600) might be directly involved in the mode of action of the unrelated antimalarial 4-aminoquinoline drug chloroquine (CQ). Along this line we report potent biochemical inhibition of membrane glutathione S-transferase activity in recombinant PfEXP1 through CQ at half maximal inhibitory CQ concentrations of 9.02 nM and 19.33 nM when using hematin and the iron deficient 1-chloro-2,4-dinitrobenzene (CDNB) as substrate, respectively. Thus, in contrast to ART, CQ may not require activation through an iron source such as hematin for a potent inhibition of membrane GST activity. Arguably, these data represent the first instance of low nanomolar inhibition of an essential Plasmodium falciparum enzyme through a 4-aminoquinoline and might encourage further investigation of PfEXP1 as a potential CQ target candidate.

Keywords: Chloroquine; Drug targets; Malaria; Membrane proteins.

Publication types

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

MeSH terms

  • Antigens, Protozoan / drug effects*
  • Antigens, Protozoan / genetics
  • Antimalarials / pharmacology*
  • Chloroquine / pharmacology*
  • Drug Delivery Systems
  • Drug Resistance
  • Glutathione Transferase / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Malaria, Falciparum / parasitology
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / enzymology
  • Plasmodium falciparum / genetics*

Substances

  • Antigens, Protozoan
  • Antimalarials
  • QF116 antigen, Plasmodium falciparum
  • Chloroquine
  • Glutathione Transferase