Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
ACS Chem Biol
2014 Mar 21;93:722-30. doi: 10.1021/cb4008953.
Show Gene links
Show Anatomy links
Quinine dimers are potent inhibitors of the Plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum.
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
.
???displayArticle.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 (PfCRT(CQR)) mediates CQ resistance by effluxing the drug from the parasite's digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRT(CQR) 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 PfCRT(CQR) reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRT(CQR) 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 PfCRT(CQR). This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum.
Bray,
PfCRT and the trans-vacuolar proton electrochemical gradient: regulating the access of chloroquine to ferriprotoporphyrin IX.
2006, Pubmed
Bray,
PfCRT and the trans-vacuolar proton electrochemical gradient: regulating the access of chloroquine to ferriprotoporphyrin IX.
2006,
Pubmed
Briolant,
Absence of association between piperaquine in vitro responses and polymorphisms in the pfcrt, pfmdr1, pfmrp, and pfnhe genes in Plasmodium falciparum.
2010,
Pubmed
Bröer,
Xenopus laevis Oocytes.
2003,
Pubmed
,
Xenbase
Burgess,
A chloroquine-like molecule designed to reverse resistance in Plasmodium falciparum.
2006,
Pubmed
Cooper,
Alternative mutations at position 76 of the vacuolar transmembrane protein PfCRT are associated with chloroquine resistance and unique stereospecific quinine and quinidine responses in Plasmodium falciparum.
2002,
Pubmed
Cooper,
Mutations in transmembrane domains 1, 4 and 9 of the Plasmodium falciparum chloroquine resistance transporter alter susceptibility to chloroquine, quinine and quinidine.
2007,
Pubmed
Desjardins,
Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique.
1979,
Pubmed
Dondorp,
Artemisinin resistance in Plasmodium falciparum malaria.
2009,
Pubmed
Ecker,
PfCRT and its role in antimalarial drug resistance.
2012,
Pubmed
Egan,
Haemozoin formation.
2008,
Pubmed
Ferdig,
Dissecting the loci of low-level quinine resistance in malaria parasites.
2004,
Pubmed
Fidock,
Antimalarial drug discovery: efficacy models for compound screening.
2004,
Pubmed
Fidock,
Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance.
2000,
Pubmed
Fidock,
Cycloguanil and its parent compound proguanil demonstrate distinct activities against Plasmodium falciparum malaria parasites transformed with human dihydrofolate reductase.
1998,
Pubmed
Fitch,
Ferriprotoporphyrin IX, phospholipids, and the antimalarial actions of quinoline drugs.
2004,
Pubmed
Hao,
In vitro sensitivities of Plasmodium falciparum isolates from the China-Myanmar border to piperaquine and association with polymorphisms in candidate genes.
2013,
Pubmed
Johnson,
Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents.
2004,
Pubmed
Kuriakose,
Click chemistry-derived bivalent quinine inhibitors of P-glycoprotein-mediated cellular efflux.
2012,
Pubmed
Lehane,
A verapamil-sensitive chloroquine-associated H+ leak from the digestive vacuole in chloroquine-resistant malaria parasites.
2008,
Pubmed
Lehane,
Chloroquine resistance-conferring mutations in pfcrt give rise to a chloroquine-associated H+ leak from the malaria parasite's digestive vacuole.
2008,
Pubmed
Lehane,
Efflux of a range of antimalarial drugs and 'chloroquine resistance reversers' from the digestive vacuole in malaria parasites with mutant PfCRT.
2010,
Pubmed
Martin,
The malaria parasite's chloroquine resistance transporter is a member of the drug/metabolite transporter superfamily.
2004,
Pubmed
Martin,
Saquinavir inhibits the malaria parasite's chloroquine resistance transporter.
2012,
Pubmed
,
Xenbase
Martin,
Chloroquine transport via the malaria parasite's chloroquine resistance transporter.
2009,
Pubmed
,
Xenbase
Mu,
Multiple transporters associated with malaria parasite responses to chloroquine and quinine.
2003,
Pubmed
Ncokazi,
A colorimetric high-throughput beta-hematin inhibition screening assay for use in the search for antimalarial compounds.
2005,
Pubmed
Peters,
The chemotherapy of rodent malaria. XLII. Halofantrine and halofantrine resistance.
1987,
Pubmed
Petersen,
Drug-resistant malaria: molecular mechanisms and implications for public health.
2011,
Pubmed
Phyo,
Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study.
2012,
Pubmed
Pires,
Fluorescence imaging of cellular glutathione using a latent rhodamine.
2008,
Pubmed
Pires,
Inhibition of P-glycoprotein-mediated paclitaxel resistance by reversibly linked quinine homodimers.
2009,
Pubmed
Pires,
Bivalent probes of the human multidrug transporter P-glycoprotein.
2006,
Pubmed
Sanchez,
Evidence for a substrate specific and inhibitable drug efflux system in chloroquine resistant Plasmodium falciparum strains.
2004,
Pubmed
Sanchez,
Dissecting the components of quinine accumulation in Plasmodium falciparum.
2008,
Pubmed
Sanchez,
Genetic linkage analyses redefine the roles of PfCRT and PfMDR1 in drug accumulation and susceptibility in Plasmodium falciparum.
2011,
Pubmed
Sidhu,
Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations.
2002,
Pubmed
Sidhu,
pfmdr1 mutations contribute to quinine resistance and enhance mefloquine and artemisinin sensitivity in Plasmodium falciparum.
2005,
Pubmed
Summers,
Know your enemy: understanding the role of PfCRT in drug resistance could lead to new antimalarial tactics.
2012,
Pubmed
Trape,
The public health impact of chloroquine resistance in Africa.
2001,
Pubmed
Ubben,
MMV in partnership: the Eurartesim® experience.
2013,
Pubmed
Valderramos,
Identification of a mutant PfCRT-mediated chloroquine tolerance phenotype in Plasmodium falciparum.
2010,
Pubmed
Waller,
Chloroquine resistance modulated in vitro by expression levels of the Plasmodium falciparum chloroquine resistance transporter.
2003,
Pubmed
Wong,
Modulation of multidrug resistance protein 1 (MRP1/ABCC1)-mediated multidrug resistance by bivalent apigenin homodimers and their derivatives.
2009,
Pubmed
Zishiri,
Quinoline antimalarials containing a dibemethin group are active against chloroquinone-resistant Plasmodium falciparum and inhibit chloroquine transport via the P. falciparum chloroquine-resistance transporter (PfCRT).
2011,
Pubmed
,
Xenbase
