Multiple drugs compete for transport via the plasmodium falciparum chloroquine resistance transporter at distinct but interdependent sites

• Verfasst von: Bellanca, Sebastiano [VerfasserIn]
• Verfasst von: Meyrath, Max [VerfasserIn]
• Verfasst von: Sanchez, Cecilia P. [VerfasserIn]
• Verfasst von: Lanzer, Michael [VerfasserIn]
• Titel: Multiple drugs compete for transport via the plasmodium falciparum chloroquine resistance transporter at distinct but interdependent sites
• Verf.angabe: Sebastiano Bellanca, Robert L. Summers, Max Meyrath, Anurag Dave, Megan N. Nash, Martin Dittmer, Cecilia P. Sanchez, Wilfred D. Stein, Rowena E. Martin, and Michael Lanzer
• E-Jahr: 2014
• Jahr: November 6, 2014
• Umfang: 17 S.
• Fussnoten: Gesehen am 14.10.2020
• Titel Quelle: Enthalten in: The journal of biological chemistry
• Ort Quelle: Bethesda, Md. : Soc., 1905
• Jahr Quelle: 2014
• Band/Heft Quelle: 289(2014), 52, Seite 36336-36351
• ISSN Quelle: 1083-351X
• DOI: doi:10.1074/jbc.M114.614206
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Chloroquine
• Sach-SW: Drug Resistance
• Sach-SW: Malaria
• Sach-SW: Membrane Transport
• Sach-SW: Mixed-type Inhibition
• Sach-SW: Parasitology
• Sach-SW: Quinine
• Sach-SW: Transporter
• Sach-SW: Verapamil
• K10plus-PPN: 1735527777

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.