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Chemical Proteomics and Super-resolution Imaging Reveal That Chloroquine Interacts with Plasmodium falciparum Multidrug Resistance-Associated Protein and Lipids.
- Source :
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ACS chemical biology [ACS Chem Biol] 2018 Oct 19; Vol. 13 (10), pp. 2939-2948. Date of Electronic Publication: 2018 Sep 24. - Publication Year :
- 2018
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Abstract
- It is well established that chloroquine, a quinoline antimalarial, inhibits hemozoin formation in the malaria parasite. Counterintuitively, this archetypal antimalarial is also used in the treatment of diseases in which hemozoin biocrystallization does not play a role. Hence, we decided to investigate whether chloroquine possesses binding targets other than Fe(III) protoporphyrin IX in blood stage Plasmodium falciparum parasites and whether these are related to sites of accumulation within the parasite other than the digestive vacuole. A 7-nitrobenz-2-oxa-1,3-diazole (NBD)-labeled fluorescent derivative of chloroquine, especially sensitive to regions outside the digestive vacuole and retaining the antiplasmodial pharmacophore, was synthesized to investigate subcellular localization in the parasite. Super-resolution microscopy revealed association with membranes including the parasite plasma membrane, the endoplasmic reticulum, and possibly also the mitochondrion. A drug-labeled affinity matrix was then prepared to capture protein binding targets of chloroquine. SDS-PAGE revealed a single prominent band between 200 and 250 kDa from the membrane-associated fraction. Subsequent proteomic analysis revealed that this band corresponded to P. falciparum multidrug resistance-associated protein (PfMRP1). Intrigued by this finding, we demonstrated pull-down of PfMRP1 by matrices labeled with Cinchona alkaloids quinine and quinidine. While PfMRP1 has been implicated in resistance to quinolines and other antimalarials, this is the first time that these drugs have been found to bind directly to this protein. Based on previous reports, PfMRP1, the only prominent protein found to bind to quinolines in this work, is likely to modulate the activity of these antimalarials in P. falciparum rather than act as a drug target.
- Subjects :
- 4-Chloro-7-nitrobenzofurazan chemical synthesis
4-Chloro-7-nitrobenzofurazan pharmacology
Antimalarials chemical synthesis
Antimalarials metabolism
Antimalarials pharmacology
Chloroquine chemical synthesis
Chloroquine pharmacology
Fluorescent Dyes chemical synthesis
Fluorescent Dyes metabolism
Fluorescent Dyes pharmacology
Mass Spectrometry
Microscopy, Confocal
Plasmodium falciparum chemistry
Plasmodium falciparum drug effects
Protein Binding
Proteomics methods
4-Chloro-7-nitrobenzofurazan analogs & derivatives
4-Chloro-7-nitrobenzofurazan metabolism
Chloroquine analogs & derivatives
Chloroquine metabolism
Multidrug Resistance-Associated Proteins metabolism
Protozoan Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1554-8937
- Volume :
- 13
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- ACS chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 30208272
- Full Text :
- https://doi.org/10.1021/acschembio.8b00583