ArticleThe Journal of biological chemistry2014
Multiple drugs compete for transport via the Plasmodium falciparum chloroquine resistance transporter at distinct but interdependent sites.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 43 citations in OpenAlex.
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- Collateral hypersensitivity between ZY19489 and piperaquine neutralizes PfCRT-mediated drug efflux and Plasmodium falciparum resistance.Nature communications · 2026Article
- Advancements in CRISPR-Cas Systems for Genome Editing towards Eradication of Human Microbial Pathogens.Molecular biotechnology · 2026Review
- Characterizing the quick-killing mechanism of action of azithromycin analogs against malaria parasites.Antimicrobial agents and chemotherapy · 2025Article
- The plasmepsin-piperaquine paradox persists in Plasmodium falciparum.PLoS pathogens · 2025Article
- Temporal Patterns of Haplotypic and Allelic Diversity Reflect the Changing Selection Landscape of the Malaria Parasite Plasmodium falciparum.Molecular biology and evolution · 2025Article
- Molecular basis of the functional conflict between chloroquine and peptide transport in the Malaria parasite chloroquine resistance transporter PfCRT.Nature communications · 2025Article
- Mapping the genomic landscape of multidrug resistance inScience advances · 2023Article
- pH-dependence of the Plasmodium falciparum chloroquine resistance transporter is linked to the transport cycle.Nature communications · 2023Article
- PfCRT mutations conferring piperaquine resistance in falciparum malaria shape the kinetics of quinoline drug binding and transport.PLoS pathogens · 2023Article
- Piperaquine-resistant PfCRT mutations differentially impact drug transport, hemoglobin catabolism and parasite physiology in Plasmodium falciparum asexual blood stages.PLoS pathogens · 2022Article
- The Knock-Down of the Chloroquine Resistance Transporter PfCRT Is Linked to Oligopeptide Handling in Plasmodium falciparum.Microbiology spectrum · 2022Article
- Mechanistic basis for multidrug resistance and collateral drug sensitivity conferred to the malaria parasite by polymorphisms in PfMDR1 and PfCRT.PLoS biology · 2022Article
- Amide Tethered 4-Aminoquinoline-naphthalimide Hybrids: A New Class of Possible Dual Function Antiplasmodials.ACS medicinal chemistry letters · 2020Article
- Molecular Mechanisms of Drug Resistance inAnnual review of microbiology · 2020Review
- The natural function of the malaria parasite's chloroquine resistance transporter.Nature communications · 2020Article
- Cellular thermal shift assay for the identification of drug-target interactions in the Plasmodium falciparum proteome.Nature protocols · 2020Article
- Structural and evolutionary analyses of the Plasmodium falciparum chloroquine resistance transporter.Scientific reports · 2020Article
- Article
- Phosphomimetic substitution at Ser-33 of the chloroquine resistance transporter PfCRT reconstitutes drug responses inThe Journal of biological chemistry · 2019Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mutations in the "chloroquine resistance transporter" (PfCRT) are a major determinant of drug resistance in the malaria parasite Plasmodium falciparum. We have previously shown that mutant PfCRT transports the antimalarial drug chloroquine away from its target, whereas the wild-type form of PfCRT does not. However, little is understood about the transport of other drugs via PfCRT or the mechanism by which PfCRT recognizes different substrates. Here we show that mutant PfCRT also transports quinine, quinidine, and verapamil, indicating that the protein behaves as a multidrug resistance carrier. Detailed kinetic analyses revealed that chloroquine and quinine compete for transport via PfCRT in a manner that is consistent with mixed-type inhibition. Moreover, our analyses suggest that PfCRT accepts chloroquine and quinine at distinct but antagonistically interacting sites. We also found verapamil to be a partial mixed-type inhibitor of chloroquine transport via PfCRT, further supporting the idea that PfCRT possesses multiple substrate-binding sites. Our findings provide new mechanistic insights into the workings of PfCRT, which could be exploited to design potent inhibitors of this key mediator of drug resistance.
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