Metalloporphyrins inhibit β-hematin (hemozoin) formation

Cole, Kelly A.; Ziegler, James; Evans, Cathy; Wright, David W.

doi:10.1016/s0162-0134(99)00216-0

Cited by 34 publications

(37 citation statements)

References 43 publications

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“…Under such conditions, free haem and haemarts can exert their toxicity, killing the parasite. [25]. The presence of a bulky artemisinyl group in HA and HAA at meso positions of the porphyrin ring of haem is likely to inhibit the stacking of haem molecules.…”

Section: Discussionmentioning

confidence: 99%

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Reaction of artemisinin with haemoglobin: implications for antimalarial activity

Kannan

Kumar

Sahal

et al. 2005

Biochemical Journal

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Elucidation of the principal targets of the action of the antimalarial drug artemisinin is an ongoing pursuit that is important for understanding the action of this drug and for the development of more potent analogues. We have examined the chemical reaction of Hb with artemisinin. The protein-bound haem in Hb has been found to react with artemisinin much faster than is the case with free haem. It appears that the uptake of Hb and the accumulation of artemisinin into the food vacuole, together with the preferred reactivity of artemisinin with haem in Hb, may make Hb the primary target of artemisinin's antimalarial action. Both monoalkylated (HA) and dialkylated (HAA) haem derivatives of artemisinin have been isolated. These 'haemarts' bind to PfHRP II (Plasmodium falciparum histidine-rich protein II), inhibiting haemozoin formation, and possess a significantly decreased ability to oxidize ascorbic acid. The accelerated formation of HAA from Hb is expected to decrease the ratio of haem to its alkylated derivatives. The haemarts that are generated from 'haemartoglobins' may bring about the death of malaria parasite by a two-pronged effect of stalling the formation of haemozoin by the competitive inhibition of haem binding to its templates and creating a more reducing environment that is not conducive to the formation of haemozoin.

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Section: Discussionmentioning

confidence: 99%

“…Effects of HA and HAA on P. falciparum culture Metalloporphyrins and protoporphyrins are known to inhibit haemozoin formation and to show antimalarial activity in in vitro culture assays [25][26][27]. Artemisinin is also known to inhibit parasite growth in the nanomolar concentration range.…”

Section: Synthesis Purification and Characterization Of Haamentioning

confidence: 99%

Reaction of artemisinin with haemoglobin: implications for antimalarial activity

Kannan

Kumar

Sahal

et al. 2005

Biochemical Journal

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“…The chloroquine family seems to act by forming complexes with hematin, thereby terminating hemozoin chain extention (Moreau et al 1982;Sullivan et al 1996). Previous reports suggest that metalloporphyrins are potent inhibitors of heme polymerization (Martiney et al 1996;Basilico et al 1997;Monti et al 1999;Cole et al 2000). The central metal ion plays a significant role in the efficacy of metalloporphyrins in inhibiting heme polymerization by forming a p)p interaction between heme and the metal ion (Cole et al 2000).…”

Section: Introductionmentioning

confidence: 99%

In vitro antimalarial activity of metalloporphyrins against Plasmodium falciparum

et al. 2003

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The in vitro antimalarial activity against Plasmodium falciparum and heme polymerization were evaluated for ten metalloporphyrins: gallium protoporphyrin IX (GaPPIX), sodium salt of gallium protoporphyrin IX, silver protoporphyrin IX, palladium protoporphyrin IX, cobalt protoporphyrin IX, manganese protoporphyrin IX, tin protoporphyrin IX (SnPPIX), chromium protoporphyrin IX, gallium deuteroporphyrin IX (GaDPIX) and gallium hematoporphyrin IX. Metalloporphyrins inhibited parasite growth with 50% inhibitory concentrations (IC(50)) ranging from 15.5 microM to 190 microM. In trophozoite lysate-mediated heme polymerization assays, SnPPIX, GaPPIX and GaDPIX exerted potent inhibitory activity similar to that of artemisinin and chloroquine.

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“…48 Other metal substituted porphyrins (Cr(III), Co(II), Mn(III), Cu(II), Mg(II)) also inhibit b-hematin formation, with the central metal ion playing an important role in the effectiveness of the inhibition. 49 These observations suggest aminoquinoline antimalarials are toxic via inhibition of hemozoin formation in a fashion similar to metal-substituted heme analogues. Since these analogues have differing dimerization, aggregation, and polymerization properties relative to FPIX, and since they ''poison'' these processes for FPIX, the target for chloroquine and other aminoquinolines likely includes one or more chemical forms of FPIX that is a precursor to hemozoin.…”

mentioning

confidence: 95%

Chloroquine resistance in the malarial parasite, Plasmodium falciparum

Ursos

Roepe

2002

Medicinal Research Reviews

102

111

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Malarial parasites remain a health problem of staggering proportions. Worldwide, they infect about 500 million, incapacitate tens of millions, and kill approximately 2.5 million (mostly children) annually. Four species infect humans, but most deaths are caused by one particular species, Plasmodium falciparum. The rising number of malarial deaths is due in part to increased drug resistance in P. falciparum. There are many varieties of antimalarial drug resistance, and there may very well be several molecular level contributions to each variety. This is because there are a number of different drugs with different mechanisms of action in use, and more than one molecular event may sometimes be relevant for resistance to any one class of drugs. Thus, "multidrug" resistance in a clinical setting likely entails complex combinations of overlapping resistance pathways, each specific for one class of drug, that then add together to confer the particular multidrug resistance phenotype. Nonetheless, rapid progress has been made in recent years in elucidating mechanisms of resistance to specific classes of antimalarial drugs. As one example, resistance to the antimalarial drug chloroquine, which has been the mainstay therapy for decades, is becoming well understood. This article focuses on recent advances in determining the molecular mechanism of chloroquine resistance, with particular attention to the biochemistry and biophysics of the P. falciparum digestive vacuole, wherein changes in pH have recently been found to be associated with chloroquine resistance.

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Metalloporphyrins inhibit β-hematin (hemozoin) formation

Cited by 34 publications

References 43 publications

Reaction of artemisinin with haemoglobin: implications for antimalarial activity

Reaction of artemisinin with haemoglobin: implications for antimalarial activity

In vitro antimalarial activity of metalloporphyrins against Plasmodium falciparum

Chloroquine resistance in the malarial parasite, Plasmodium falciparum

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