Chloroquine susceptibility and reversibility in a <i>Plasmodium falciparum</i> genetic cross

Patel, Jigar; Drew, Thacker; Tan, John C.; Pleeter, Perri; Checkley, Lisa A.; Gonzales, Joseph M; Deng, Bingbing; Roepe, Paul D.; Cooper, Roland A.; Ferdig, Michael T.

doi:10.1111/j.1365-2958.2010.07366.x

Cited by 51 publications

(66 citation statements)

References 106 publications

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“…By contrast, at the same concentration, CP and its derivatives had no effect on the proliferation of CQS C2 GC03 parasites, yet all displayed significant inhibitory activity against the CQR C4 Dd2 and C6 7G8 lines (Table 2; P < 0.05). This finding is consistent with previous observations of resistance-reversers displaying modest but significant levels of intrinsic antiplasmodial activity against CQR strains 26 (while exerting little or no effect in CQS strains) and provides further support for the idea that PfCRT CQR could be viewed as a drug target. 8 None of the test compounds affected the IC 50 of CQ against CQS C2 GC03 parasites (Table 2; P > 0.2).…”

Section: 11supporting

confidence: 92%

Chlorpheniramine Analogues Reverse Chloroquine Resistance inPlasmodium falciparumby Inhibiting PfCRT

Deane

Summers

Lehane

et al. 2014

ACS Med. Chem. Lett.

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ABSTRACT:The emergence and spread of malaria parasites that are resistant to chloroquine (CQ) has been a disaster for world health. The antihistamine chlorpheniramine (CP) partially resensitizes CQ-resistant (CQR) parasites to CQ but possesses little intrinsic antiplasmodial activity. Mutations in the parasite's CQ resistance transporter (PfCRT) confer resistance to CQ by enabling the protein to transport the drug away from its site of action, and it is thought that resistance-reversers such as CP exert their effect by blocking this CQ transport activity. Here, a series of new structural analogues and homologues of CP have been synthesized. We show that these compounds (along with other in vitro CQ resistance-reversers) inhibit the transport of CQ via a resistanceconferring form of PfCRT expressed in Xenopus laevis oocytes. Furthermore, the level of PfCRT-inhibition was found to correlate well with both the restoration of CQ accumulation and the level of CQ resensitization in CQR parasites.KEYWORDS: Malaria parasite, chloroquine resistance, chemosensitization, chlorpheniramine, PfCRT, Xenopus oocytes T he malaria parasite Plasmodium falciparum has proven largely refractory to the vaccine approaches trialled to date and reliance on chemotherapy is under serious threat with the recent emergence of parasites that are resistant to the current mainstay of malaria treatment (the artemisinin-based combination therapies).1 As a result, malaria remains a global health problem; there are around 225 million clinical cases and over 1.2 million deaths each year, 2 and the disease also imposes considerable socio-economic burdens upon afflicted countries. Chloroquine (CQ, Figure 1A) was a cheap, safe, and efficacious treatment for the disease until the eventual emergence and spread of resistant parasites. Resistance to CQ is caused primarily by mutations in the P. falciparum CQ resistance transporter, PfCRT.3 Within the P. falciparum-infected erythrocyte, PfCRT is found in the membrane of the parasite's digestive vacuole 4 (DV; pH 5−5.5); the organelle in which CQ accumulates and exerts its antimalarial effect. Mutations in PfCRT that confer CQ resistance result in a marked reduction in the accumulation of CQ within the DV. Using the Xenopus laevis oocyte expression system, a CQ resistance-conferring form of PfCRT (PfCRT CQR ) was shown to transport CQ, whereas the wild-type form found in CQ-sensitive (CQS) parasites (PfCRT CQS ) lacked this ability. 5Mutations in PfCRT have been associated with decreases or increases in the parasite's susceptibility to other antimalarials, 6 and the transporter has been shown to be one of the key determinants of the parasite's response to a diverse set of novel antiplasmodial compounds. 7 Whether these effects are due to PfCRT-mediated drug efflux and/or the inhibition of the transporter's normal function (which is essential for the survival of the parasite, but currently unknown) remains unclear.8 A better understanding of the interactions between PfCRT CQR and its substrates and inhibitors ...

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Section: 11supporting

confidence: 92%

Chlorpheniramine Analogues Reverse Chloroquine Resistance inPlasmodium falciparumby Inhibiting PfCRT

Deane

Summers

Lehane

et al. 2014

ACS Med. Chem. Lett.

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“…In the present study, RCQ IC 50 s in P. vivax were lower than those of CQ, which suggests that the resistance reverser moiety of the RCQ compounds does have an effect on CQ activity in P. vivax isolates. The mechanisms of both CQ resistance and CQ resistance reversal activity of various chemosensitizers have been investigated in P. falciparum and revealed pfcrt to be a key determinant of resistance and a target for chemosensitizers; however, both processes are likely to be mediated by multiple factors (5,22,23). The knowledge of these processes in P. vivax is still elusive.…”

Section: Discussionmentioning

confidence: 99%

Contrasting Ex Vivo Efficacies of “Reversed Chloroquine” Compounds in Chloroquine-Resistant Plasmodium falciparum and P. vivax Isolates

Wirjanata

Sebayang

Chalfein

et al. 2015

Antimicrob Agents Chemother

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h Chloroquine (CQ) has been the mainstay of malaria treatment for more than 60 years. However, the emergence and spread of CQ resistance now restrict its use to only a few areas where malaria is endemic. The aim of the present study was to investigate whether a novel combination of a CQ-like moiety and an imipramine-like pharmacophore can reverse CQ resistance ex vivo. Between March to October 2011 and January to September 2013, two "reversed chloroquine" (RCQ) compounds (PL69 and PL106) were tested against multidrug-resistant field isolates of Plasmodium falciparum (n ‫؍‬ 41) and Plasmodium vivax (n ‫؍‬ 45) in Papua, Indonesia, using a modified ex vivo schizont maturation assay. The RCQ compounds showed high efficacy against both CQ-resistant P. falciparum and P. vivax field isolates. For P. falciparum, the median 50% inhibitory concentrations (IC 50 s) were 23.2 nM for PL69 and 26.6 nM for PL106, compared to 79.4 nM for unmodified CQ (P < 0.001 and P ‫؍‬ 0.036, respectively). The corresponding values for P. vivax were 19.0, 60.0, and 60.9 nM (P < 0.001 and P ‫؍‬ 0.018, respectively). There was a significant correlation between IC 50 s of CQ and PL69 (Spearman's rank correlation coefficient [r s ] ‫؍‬ 0.727, P < 0.001) and PL106 (r s ‫؍‬ 0.830, P < 0.001) in P. vivax but not in P. falciparum. Both RCQs were equally active against the ring and trophozoite stages of P. falciparum, but in P. vivax, PL69 and PL106 showed less potent activity against trophozoite stages (median IC 50 s, 130.2 and 172.5 nM) compared to ring stages (median IC 50 s, 17.6 and 91.3 nM). RCQ compounds have enhanced ex vivo activity against CQ-resistant clinical isolates of P. falciparum and P. vivax, suggesting the potential use of reversal agents in antimalarial drug development. Interspecies differences in RCQ compound activity may indicate differences in CQ pharmacokinetics between the two Plasmodium species.

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“…Recently, polymorphisms in a P. falciparum-encoded Na ϩ /H ϩ exchanger, PfNHE-1, were linked to in vitro QN susceptibility in laboratory-adapted and clinical isolates in some studies, but not in others (3,10,24,31,50). Neither mutations in pfnhe-1 or pfmdr1 nor gene copy number in the latter are known to influence stereospecific responses to CA (7,24,49,59). Our findings support PfCRT as a major parasite-encoded determinant of CA susceptibility and stereospecificity, although additional genes, gene interactions, and other genomic changes likely contribute parasite responses to the CA (24,33).…”

Section: Discussionmentioning

confidence: 99%

Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids

Griffin

Hoke

Samarakoon

et al. 2012

Antimicrob Agents Chemother

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eThe Cinchona alkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (؊)-quinine and (؉)-quinidine. The potency of (؉)-isomers is greater than the (؊)-isomers in vitro and in vivo against Plasmodium falciparum malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparum chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward P. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the in vitro susceptibility of eight clonal lines of P. falciparum derived from the 106/1 strain, each containing a unique pfcrt allele, to four Cinchona stereoisomer pairs: quinine and quinidine; cinchonidine and cinchonine; hydroquinine and hydroquinidine; 9-epiquinine and 9-epiquinidine. Stereospecific potency of the Cinchona alkaloids was associated with changes in charge and hydrophobicity of mutable PfCRT amino acids. In isogenic chloroquine-resistant lines, the IC 50 ratio of (؊)/(؉) CA pairs correlated with side chain hydrophobicity of the position 76 residue. Second-site PfCRT mutations negated the K76I stereospecific effects: charge-change mutations C72R or Q352K/R restored potency patterns similar to the parent K76 line, while V369F increased susceptibility to the alkaloids and nullified stereospecific differences between alkaloid pairs. Interactions between key residues of the PfCRT channel/transporter with (؊) and (؉) alkaloids are stereospecifically determined, suggesting that PfCRT binding plays an important role in the antimalarial activity of quinine and other Cinchona alkaloids.A lkaloids from the Cinchona tree, exemplified by quinine (QN) and quinidine (QD), have proven to be an important source of antimalarial therapies, especially after resistance to chloroquine (CQ) emerged. QN remains a first-line drug in the treatment of severe malaria in many parts of the world, even with increased use of artemisinin-based combination therapies (70). The Cinchona alkaloids (CA) are aryl amino alcohols where the aryl group is a quinoline (quinoline aminoalcohols). They have four chiral centers, two of which, C-8 and C-9, can have different configurations (66) (Fig. 1). Among the pharmacologically active 8,9-erythro isomers, QN, hydroquinine (HQN), and cinchonidine (CD) all present the S configuration around C-8 and the R configuration at C-9 and are levorotatory (rotate plane polarized light in an anticlockwise [Ϫ] direction). The reverse ordering, R at C-8 and S at C-9, occurs in the respective dextrorotatory (rotate plane polarized light in a clockwise [ϩ] direction) diastereomers, QD, hydroquinidine (HQD), and cinchonine (CN). The 8,9-threo diastereomers 9-epiquinine (EQN) and 9-epiquinidine (EQD) are 8S, 9S, and 8R, 9R, respectively.Against Plasmodium falciparum, the CA diastereomer pairs have a well-established in ...

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Chloroquine susceptibility and reversibility in a Plasmodium falciparum genetic cross

Cited by 51 publications

References 106 publications

Chlorpheniramine Analogues Reverse Chloroquine Resistance inPlasmodium falciparumby Inhibiting PfCRT

Chlorpheniramine Analogues Reverse Chloroquine Resistance inPlasmodium falciparumby Inhibiting PfCRT

Contrasting Ex Vivo Efficacies of “Reversed Chloroquine” Compounds in Chloroquine-Resistant Plasmodium falciparum and P. vivax Isolates

Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids

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