| Autor: |
Andreas Martin Lisewski, Joel Patrick Quiros, Monica Mittal, Nagireddy Putluri, Arun Sreekumar, Jesper Z. Haeggström, Olivier Lichtarge |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
|
| Zdroj: |
International Journal for Parasitology: Drugs and Drug Resistance, Vol 8, Iss 1, Pp 31-35 (2018) |
| Druh dokumentu: |
article |
| ISSN: |
2211-3207 |
| DOI: |
10.1016/j.ijpddr.2017.12.003 |
| Popis: |
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: Malaria, Drug targets, Chloroquine, Membrane proteins |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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