Photoaffinity labeling of mefloquine-binding proteins in human serum, uninfected erythrocytes and Plasmodium falciparum-infected erythrocytes

Desneves, José; Thorn, George W.; Berman, A. L.; Galatis, Denise; Greca, Nadia La; Sinding, J.; Foley, Michael; Deady, Leslie W.; Cowman, Alan F.; Tilley, Leann

doi:10.1016/0166-6851(96)02732-6

Cited by 23 publications

(15 citation statements)

References 36 publications

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“…Therefore, the observation that the incorporation of a radiolabelled drug (CQ, QN, or MQ) into the growing hemozoin polymers is almost completely arrested in the presence of Ro40-4388 would suggest that it is the interaction of the drug with the heme monomer or polymer which is central to activity, rather than any secondary effect on heme polymerization. This is in keeping with many of the hypotheses put forward to explain the antimalarial activities of these drugs over the years (5,7,13) and argues against the need to invoke different mechanisms of action for the 4-aminoquinolines and the quinoline or phenanthrene methanols, as has been suggested (10,14). The facts that PQ does not inhibit hematin polymerization (12) and that it most likely exerts its antimalarial action via a hemeindependent mechanism (12) give support to the use of PQ as a control in this study.…”

Section: Discussionsupporting

confidence: 61%

“…MQ is a monoprotic weak base which should accumulate less well than CQ; nevertheless, it shows similar 50% inhibitory concentration (IC 50 ) values in vitro. This evidence has been the basis for questioning whether these drugs interact at different points within the hemoglobin degradation process or if MQ has an additional or an independent mechanism of action distinct from that of AQ and CQ (10,14).…”

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confidence: 99%

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Central Role of Hemoglobin Degradation in Mechanisms of Action of 4-Aminoquinolines, Quinoline Methanols, and Phenanthrene Methanols

Mungthin

Bray

Ridley

et al. 1998

Antimicrob Agents Chemother

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We have used a specific inhibitor of the malarial aspartic proteinase plasmepsin I and a nonspecific cysteine proteinase inhibitor to investigate the importance of hemoglobin degradation in the mechanism of action of chloroquine, amodiaquine, quinine, mefloquine (MQ), halofantrine, and primaquine. Both proteinase inhibitors antagonized the antiparasitic activity of all drugs tested with the exception of primaquine. An inhibitor of plasmepsin I, Ro40-4388, reduced the incorporation of radiolabelled chloroquine and quinine into malarial pigment by 95%, while causing a 70% reduction in the incorporation of radiolabelled MQ. Cysteine proteinase inhibitor E64 reduced the incorporation of chloroquine and quinine into malarial pigment by 60 and 40%, respectively. This study provides definitive support for the central role of hemoglobin degradation in the mechanism of action of the 4-aminoquinolines and the quinoline and phenanthrene methanol antimalarials.

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Section: Discussionsupporting

confidence: 61%

mentioning

confidence: 99%

Central Role of Hemoglobin Degradation in Mechanisms of Action of 4-Aminoquinolines, Quinoline Methanols, and Phenanthrene Methanols

Mungthin

Bray

Ridley

et al. 1998

Antimicrob Agents Chemother

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“…The failure to detect preferential, MQ-inhibitable labeling of Pgh1 by the probe could indicate that Pgh1 does not interact directly with MQ. However, the photoreactive analogue had only 1/10 of the antiplasmodial activity of MQ, and the authors caution that the technique may not have been sufficiently sensitive to detect a preferential interaction of the probe with Pgh1 given the low abundance of the protein in the parasite (6). The data therefore do not exclude the possibility that MQ interacts with Pgh1 directly.…”

mentioning

confidence: 64%

“…It should be noted that a photoreactive analogue of MQ used to attempt to identify the targets of the drug in P. falciparum labeled a protein of the same size as Pgh1 only weakly (6). The failure to detect preferential, MQ-inhibitable labeling of Pgh1 by the probe could indicate that Pgh1 does not interact directly with MQ.…”

mentioning

confidence: 99%

Mutations in pfmdr1 Modulate the Sensitivity of Plasmodium falciparum to the Intrinsic Antiplasmodial Activity of Verapamil

Hayward

Saliba

Kirk

2005

Antimicrob Agents Chemother

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As well as having the ability to reverse chloroquine resistance in the human malaria parasite Plasmodium falciparum, verapamil has itself an innate antiplasmodial activity. We show here that mutations in Pgh1, the product of the malaria parasite's pfmdr1 gene, influence the parasite's susceptibility to the toxic effects of verapamil.Verapamil (VP) is a weak base which, in addition to acting as a reverser of chloroquine resistance (CQR) in the malaria parasite Plasmodium falciparum, has itself an intrinsic antiplasmodial activity (1,12,14,26). This activity is independent of its CQR reversal effect, as the susceptibility of chloroquine (CQ)-sensitive parasites to CQ is unaltered even in the presence of highly toxic concentrations of VP, whereas VP alters the susceptibility of CQ-resistant parasites to CQ at both toxic and nontoxic concentrations (15). The CQR reversal effect of VP has been attributed to an interaction of the compound with the P. falciparum chloroquine resistance transporter (PfCRT) (7,17,23), a member of the drug-metabolite transporter superfamily (13, 25) which is localized to the parasite's internal digestive vacuole and is the key determinant of CQR (8,23).Recent allelic exchange experiments have shown that mutations in the pfmdr1 gene product, P-glycoprotein homologue 1 (Pgh1), modulate sensitivity to a range of antimalarial compounds (20). Pgh1 is localized predominantly to the parasite's digestive vacuole membrane (4, 10). It belongs to the ATPbinding cassette transporter superfamily, members of which couple ATP hydrolysis to the translocation of a diverse range of structurally unrelated solutes across cell membranes (reviewed in reference 11). We report here that polymorphisms in pfmdr1 influence the parasite's susceptibility to the intrinsic antiplasmodial effect of VP.Transfected P. falciparum parasites derived from either D10 (CQ-sensitive) or 7G8 (CQ-resistant) strains with pfmdr1 loci altered as described previously (20) The introduction of either one or three of the four 7G8 mutations into the pfmdr1 gene of the D10 parasite (to make D10-mdr 7G8/1 or D10-mdr 7G8/3 ) significantly increased VP sensitivity with respect to the D10-mdr D10 transfectant, a control transfectant with the wild-type pfmdr1 gene (Table 1). Notably, D10-mdr 7G8/1 , with a single mutation at codon 1246, was more sensitive to VP than D10-mdr 7G8/3 , which carries two additional mutations at codons 1034 and 1042. Replacement of these three mutations in the 7G8 parasite with the corresponding wild-type D10 pfmdr1 sequence (7G8-mdr D10 ) was sufficient to confer full D10-like tolerance to VP. Further analysis shows that the pattern of relative sensitivity of these transfectants to VP correlates significantly with the pattern of sensitivity to mefloquine (MQ) and halofantrine (HF) obtained in a previous study (20) (r 2 ϭ 0.82 and P ϭ 0.035 in both cases). This result suggests that specific mutations in pfmdr1 mediate sensitivity to these compounds via a common mechanism. There is no difference in the levels of Pgh1 ...

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“…Both drugs are highly lipophilic and it is known that halofantrine binds extensively to lipoproteins ( Cenni et al ., 1995 ; Humberstone et al ., 1998 ). Mefloquine has also been reported to bind to lipoproteins ( Desneves et al ., 1996 ). If mefloquine limited the binding of halofantrine to lipoproteins this could have reduced the amount of halofantrine being removed from the circulation by the uptake of lipoproteins into tissues.…”

Section: Discussionmentioning

confidence: 99%

Potentiation of halofantrine‐induced QTc prolongation by mefloquine: correlation with blood concentrations of halofantrine

Lightbown

Lambert

Edwards

et al. 2001

British J Pharmacology

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1 The antimalarial drug halofantrine can prolong the QT interval and this may be enhanced by prior use of me¯oquine. This possible interaction has been investigated by examining the e ects of halofantrine and me¯oquine alone and in combination. 2 In anaesthetized rabbits (n=6 per group), halofantrine given as bolus doses of 1, 3, 10, and 30 mg kg 71 at 25 min intervals dose-dependently prolonged the rate-corrected QT (QTc) interval from 313+12 ms pre-drug to 410+18 ms after the highest dose. Similar doses of me¯oquine did not alter QTc intervals signi®cantly. The highest dose of me¯oquine (30 mg kg 71 ) caused cardiac contractile failure. 3 Pretreatment with 3 mg kg 71 me¯oquine 25 min before the ®rst dose of halofantrine potentiated the e ects of all doses of halofantrine on QTc intervals. 4 The blood concentrations of halofantrine were two to six times higher in the group pretreated with me¯oquine compared to the halofantrine alone group; e.g. 1.03+0.17 and 0.16+0.02 mM respectively after 1 mg kg 71 halofantrine. There was a signi®cant correlation between blood halofantrine concentrations and QTc intervals (r=0.673). Even after making allowance for overestimation of the potency of halofantrine that may result from the hypokalaemia that is prevalent in anaesthetized rabbits, these e ects occurred with concentrations of halofantrine that are found in clinical use. 5 These data indicate clearly that while me¯oquine does not alter QTc intervals itself, it does enhance the e ects of halofantrine by increasing the circulating concentration of halofantrine.

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Photoaffinity labeling of mefloquine-binding proteins in human serum, uninfected erythrocytes and Plasmodium falciparum-infected erythrocytes

Cited by 23 publications

References 36 publications

Central Role of Hemoglobin Degradation in Mechanisms of Action of 4-Aminoquinolines, Quinoline Methanols, and Phenanthrene Methanols

Central Role of Hemoglobin Degradation in Mechanisms of Action of 4-Aminoquinolines, Quinoline Methanols, and Phenanthrene Methanols

Mutations in pfmdr1 Modulate the Sensitivity of Plasmodium falciparum to the Intrinsic Antiplasmodial Activity of Verapamil

Potentiation of halofantrine‐induced QTc prolongation by mefloquine: correlation with blood concentrations of halofantrine

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