Quinine dimers are potent inhibitors of the plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum

Christine A. Hrycyna, Robert L. Summers, Adele M. Lehane, Marcos M. Pires, Hilda Namanja, Kelsey Bohn, Jerrin Kuriakose, Michael Ferdig, Philipp P. Henrich, David A. Fidock, Kiaran Kirk, Jean Chmielewski, Rowena E. Martin

Research output: Contribution to journalArticle

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Abstract

Chloroquine (CQ) resistance in the human malaria parasite Plasmodium falciparum is primarily conferred by mutations in the "chloroquine resistance transporter" (PfCRT). The resistance-conferring form of PfCRT (PfCRTCQR) mediates CQ resistance by effluxing the drug from the parasite's digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRTCQR can also decrease the parasite's susceptibility to other quinoline drugs, including the current antimalarials quinine and amodiaquine. Here we describe interactions between PfCRT CQR and a series of dimeric quinine molecules using a Xenopus laevis oocyte system for the heterologous expression of PfCRT and using an assay that detects the drug-associated efflux of H+ ions from the digestive vacuole in parasites that harbor different forms of PfCRT. The antiplasmodial activities of dimers 1 and 6 were also examined in vitro (against drug-sensitive and drug-resistant strains of P. falciparum) and in vivo (against drug-sensitive P. berghei). Our data reveal that the quinine dimers are the most potent inhibitors of PfCRTCQR reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRTCQR from the digestive vacuole but instead accumulated to very high levels within this organelle. Both 1 and 6 exhibited in vitro antiplasmodial activities that were inversely correlated with CQ. Moreover, the additional parasiticidal effect exerted by 1 and 6 in the drug-resistant parasites was attributable, at least in part, to their ability to inhibit PfCRTCQR. This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum.

Original languageEnglish (US)
Pages (from-to)722-730
Number of pages9
JournalACS Chemical Biology
Volume9
Issue number3
DOIs
StatePublished - Mar 21 2014
Externally publishedYes

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Quinine
Plasmodium falciparum
Dimers
Chloroquine
Parasites
Vacuoles
Pharmaceutical Preparations
Antimalarials
Amodiaquine
Lead compounds
Falciparum Malaria
Xenopus laevis
Drug Resistance
Organelles
Oocytes
Ports and harbors
quinoline
Plasmodium falciparum PfCRT protein
Assays
Ions

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Quinine dimers are potent inhibitors of the plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum. / Hrycyna, Christine A.; Summers, Robert L.; Lehane, Adele M.; Pires, Marcos M.; Namanja, Hilda; Bohn, Kelsey; Kuriakose, Jerrin; Ferdig, Michael; Henrich, Philipp P.; Fidock, David A.; Kirk, Kiaran; Chmielewski, Jean; Martin, Rowena E.

In: ACS Chemical Biology, Vol. 9, No. 3, 21.03.2014, p. 722-730.

Research output: Contribution to journalArticle

Hrycyna, CA, Summers, RL, Lehane, AM, Pires, MM, Namanja, H, Bohn, K, Kuriakose, J, Ferdig, M, Henrich, PP, Fidock, DA, Kirk, K, Chmielewski, J & Martin, RE 2014, 'Quinine dimers are potent inhibitors of the plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum', ACS Chemical Biology, vol. 9, no. 3, pp. 722-730. https://doi.org/10.1021/cb4008953
Hrycyna, Christine A. ; Summers, Robert L. ; Lehane, Adele M. ; Pires, Marcos M. ; Namanja, Hilda ; Bohn, Kelsey ; Kuriakose, Jerrin ; Ferdig, Michael ; Henrich, Philipp P. ; Fidock, David A. ; Kirk, Kiaran ; Chmielewski, Jean ; Martin, Rowena E. / Quinine dimers are potent inhibitors of the plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum. In: ACS Chemical Biology. 2014 ; Vol. 9, No. 3. pp. 722-730.
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AU - Hrycyna, Christine A.

AU - Summers, Robert L.

AU - Lehane, Adele M.

AU - Pires, Marcos M.

AU - Namanja, Hilda

AU - Bohn, Kelsey

AU - Kuriakose, Jerrin

AU - Ferdig, Michael

AU - Henrich, Philipp P.

AU - Fidock, David A.

AU - Kirk, Kiaran

AU - Chmielewski, Jean

AU - Martin, Rowena E.

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N2 - Chloroquine (CQ) resistance in the human malaria parasite Plasmodium falciparum is primarily conferred by mutations in the "chloroquine resistance transporter" (PfCRT). The resistance-conferring form of PfCRT (PfCRTCQR) mediates CQ resistance by effluxing the drug from the parasite's digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRTCQR can also decrease the parasite's susceptibility to other quinoline drugs, including the current antimalarials quinine and amodiaquine. Here we describe interactions between PfCRT CQR and a series of dimeric quinine molecules using a Xenopus laevis oocyte system for the heterologous expression of PfCRT and using an assay that detects the drug-associated efflux of H+ ions from the digestive vacuole in parasites that harbor different forms of PfCRT. The antiplasmodial activities of dimers 1 and 6 were also examined in vitro (against drug-sensitive and drug-resistant strains of P. falciparum) and in vivo (against drug-sensitive P. berghei). Our data reveal that the quinine dimers are the most potent inhibitors of PfCRTCQR reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRTCQR from the digestive vacuole but instead accumulated to very high levels within this organelle. Both 1 and 6 exhibited in vitro antiplasmodial activities that were inversely correlated with CQ. Moreover, the additional parasiticidal effect exerted by 1 and 6 in the drug-resistant parasites was attributable, at least in part, to their ability to inhibit PfCRTCQR. This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum.

AB - Chloroquine (CQ) resistance in the human malaria parasite Plasmodium falciparum is primarily conferred by mutations in the "chloroquine resistance transporter" (PfCRT). The resistance-conferring form of PfCRT (PfCRTCQR) mediates CQ resistance by effluxing the drug from the parasite's digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRTCQR can also decrease the parasite's susceptibility to other quinoline drugs, including the current antimalarials quinine and amodiaquine. Here we describe interactions between PfCRT CQR and a series of dimeric quinine molecules using a Xenopus laevis oocyte system for the heterologous expression of PfCRT and using an assay that detects the drug-associated efflux of H+ ions from the digestive vacuole in parasites that harbor different forms of PfCRT. The antiplasmodial activities of dimers 1 and 6 were also examined in vitro (against drug-sensitive and drug-resistant strains of P. falciparum) and in vivo (against drug-sensitive P. berghei). Our data reveal that the quinine dimers are the most potent inhibitors of PfCRTCQR reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRTCQR from the digestive vacuole but instead accumulated to very high levels within this organelle. Both 1 and 6 exhibited in vitro antiplasmodial activities that were inversely correlated with CQ. Moreover, the additional parasiticidal effect exerted by 1 and 6 in the drug-resistant parasites was attributable, at least in part, to their ability to inhibit PfCRTCQR. This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum.

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