Potential role of Plasmodium falciparum exported protein 1 in the chloroquine mode of action

Publication date: April 2018Source: International Journal for Parasitology: Drugs and Drug Resistance, Volume 8, Issue 1Author(s): Andreas Martin Lisewski, Joel Patrick Quiros, Monica Mittal, Nagireddy Putluri, Arun Sreekumar, Jesper Z. Haeggström, Olivier LichtargeAbstractIn 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 ...
Source: International Journal for Parasitology: Drugs and Drug Resistance - Category: Parasitology Source Type: research