The interaction of artemisinin with malarial hemozoin

Hong, Yulong; Yang, Ying; Meshnick, Steven R.

doi:10.1016/0166-6851(94)90014-0

Cited by 169 publications

(139 citation statements)

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“…The alkylation of haem by artemisinin has been well characterized, and it is clear that haem is both the initiator as well as the target of artemisinin action [9,22,35]. Other possible targets of artemisinin are specific parasite proteins, although no details have been reported for such artemisinin-protein adducts.…”

Section: Discussionmentioning

confidence: 99%

“…This cleavage of the peroxide is mediated by iron, which makes iron a necessity in the early onset of artemisinin action [32,33]. In fact, the oxidizing effects of artemisinin on parasitic membranes are greatly enhanced in the presence of haem [34], and haem itself is known to react with artemisinin [9,22,35]. Although a general notion about artemisinin action is that haem iron is central to its action, the relative effects of free haem and protein-bound haems with regard to reactivity with artemisinin have remained unclear.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, we found that, like HA, HAA also binds to PfHRP II. It is believed that artemisinin interferes with the process of haem detoxification, and this may constitute at least one of the many mechanisms of the action of this drug [9,22]. Alkylation of haem to HA introduces a haem mimic that interferes with the formation of haemozoin [9].…”

Section: Discussionmentioning

confidence: 99%

“…Specific reactions of artemisinin with TCTP (translationally controlled tumour protein) [19], inhibition of the SERCA (sarcoplasmic/endoplasmic-reticulum Ca 2+ -ATPase) orthologue (PfATP6) of P. falciparum [20] and inhibition of P. falciparum cysteine proteases have also been proposed to contribute to its drug activity [21]. On the other hand, Hong et al [22] reported that artemisinin forms covalent adducts with haem in artemisinintreated parasite cultures.…”

Section: Introductionmentioning

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%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…The mechanism of action of artemisinin derivatives is thought to involve the interac-tion between the drugs and hemin within the digestive vacuole of the parasite. [45][46][47][48] The iron-dependent decomposition of artemisinin generates free oxygen radicals that destroy the parasites. The 4-aminoquinolines and aminoalcohols also concentrate within the digestive vacuole but their precise mode of action has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon.

Ringwald¹,

Bickii²,

Basco³

1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. The in vitro activities of dihydroartemisinin (the biologically active metabolite of artemisinin derivatives), chloroquine, monodesethylamodiaquine (the biologically active metabolite of amodiaquine), quinine, mefloquine, halofantrine, and pyrimethamine were assessed in 65 African isolates of Plasmodium falciparum from Yaoundé, Cameroon using an isotopic microtest. The 50% inhibitory concentration (IC 50 ) values for dihydroartemisinin were within a narrow range from 0.25 to 4.56 nM, with a geometric mean of 1.11 nM (95% confidence interval ϭ 0.96-1.28 nM). Dihydroartemisinin was equally active (P Ͼ 0.05) against the chloroquine-sensitive isolates (geometric mean IC 50 ϭ 1.25 nM, 95% confidence interval ϭ 0.99-1.57 nM) and the chloroquine-resistant isolates (geometric mean IC 50 ϭ 0.979 nM, 95% confidence interval ϭ 0.816-1.18 nM). A significant positive correlation was observed between the responses to dihydroartemisinin and mefloquine (r ϭ 0.662) or halofantrine (r ϭ 0.284), suggesting in vitro crossresistance. There was no correlation between the responses to dihydroartemisinin and other antimalarial drugs.Artemisinin (qinghaosu) has been used for centuries in traditional Chinese medicine for antimalarial treatment. 1 In 1972, Chinese scientists isolated the active principle from the plant Artemisia annua. 2 Artemisinin is a sesquiterpene lactone characterized by the presence of an endoperoxide that is associated with a potent antimalarial activity. Because artemisinin is chemically unstable and poorly soluble in water or oil, the carbonyl group at C-10 of the parent compound was reduced to obtain dihydroartemisinin. Several derivatives have been developed by adding an ether, ester, or other substituents to the hydroxyl group of dihydroartemisinin. These semi-synthetic derivatives include the water-soluble derivatives, sodium artesunate and artelinic acid, and the oilsoluble derivatives, artemether and arteether. With the exception of arteether and artelinic acid, these compounds are used to treat malarial infections in endemic countries, mainly in Southeast Asia and, to a lesser extent, in Africa and South America.Artemisinin derivatives are available in different formulations for oral, parenteral, and rectal administration. Clinical studies have shown that artemisinin derivatives are highly potent, rapidly acting, and well-tolerated blood schizontocides, resulting in shorter parasite clearance times than other antimalarial drugs. 3,4 Artemisinin derivatives are highly effective against Plasmodium falciparum isolates that are resistant to other drugs. These derivatives are indicated for the emergency treatment of severe and complicated falciparum malaria by parenteral administration and for the oral treatment of uncomplicated multidrug-resistant malaria. 5 So far, resistance to artemisinin derivatives has not been reported in clinical studies. However, because of the high recrudescence rate when used as monotherapy, many current therapeutic regimens used in Southeast Asia include a combination of o...

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Alkylating Properties of Antimalarial Artemisinin Derivatives and Synthetic Trioxanes when Activated by a Reduced Heme Model

Robert

Meunier

1998

Chem. Eur. J.

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Three potent antimalarial drugs bearing a trioxane function, artemisinin, b-artemether, and a synthetic analogue BO7, were found to behave as alkylating agents towards a heme model, meso-tetraphenylporphyrin. The covalent chlorin ± drug adducts obtained between these drugs and the macrocycle were completely characterized. These adducts resulted from a C-alkylation of a b-pyrrolic position of the porphyrin macrocycle by a C-centered radical produced by the reductive homolytic cleavage of the peroxide bridge of artemisinin or its analogues. The results indicate that the alkylating properties of artemisinin, which are considered to be responsible for the death of the parasite, are not limited to this natural compound, but are a common feature probably required for the antimalarial activity of endoperoxide-containing drugs.

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The interaction of artemisinin with malarial hemozoin

Cited by 169 publications

References 17 publications

Reaction of artemisinin with haemoglobin: implications for antimalarial activity

Reaction of artemisinin with haemoglobin: implications for antimalarial activity

In vitro activity of dihydroartemisinin against clinical isolates of Plasmodium falciparum in Yaounde, Cameroon.

Alkylating Properties of Antimalarial Artemisinin Derivatives and Synthetic Trioxanes when Activated by a Reduced Heme Model

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