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 language | English (US) |
|---|---|
| Pages (from-to) | 722-730 |
| Number of pages | 9 |
| Journal | ACS Chemical Biology |
| Volume | 9 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 21 2014 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Quinine dimers are potent inhibitors of the plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum
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.
PY - 2014/3/21
Y1 - 2014/3/21
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.
UR - http://www.scopus.com/inward/record.url?scp=84896949152&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84896949152&partnerID=8YFLogxK
U2 - 10.1021/cb4008953
DO - 10.1021/cb4008953
M3 - Article
C2 - 24369685
AN - SCOPUS:84896949152
VL - 9
SP - 722
EP - 730
JO - ACS Chemical Biology
JF - ACS Chemical Biology
SN - 1554-8929
IS - 3
ER -