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1.
Stanley Mukanganyama Yogeshkumar S. Naik Mikael Widersten Bengt Mannervik Julia A. Hasler 《Free radical research》2001,35(4):427-434
Artemisinin is a sesquiterpene lactone containing an endoperoxide bridge. It is a promising new antimalarial and is particularly useful against the drug resistant strains of Plasmodium falciparum. It has unique antimalarial properties since it acts through the generation of free radicals that alkylate parasite proteins. Since the antimalarial action of the drug is antagonised by glutathione and ascorbate and has unusual pharmacokinetic properties in humans, we have investigated if the drug is broken down by a typical reductive reaction in the presence of glutathione transferases. Cytosolic glutathione transferases (GSTs) detoxify electrophilic xenobiotics by catalysing the formation of glutathione (GSH) conjugates and exhibit glutathione peroxidase activity towards hydroperoxides. Artemisinin was incubated with glutathione, NADPH and glutathione reductase and GSTs in a coupled assay system analogous to the standard assay scheme with cumene hydroperoxide as a substrate of GSTs. Artemisinin was shown to stimulate NADPH oxidation in cytosols from rat liver, kidney, intestines and in affinity purified preparations of GSTs from rat liver. Using human recombinant GSTs hetelorogously expressed in Escherichia coli, artemisinin was similarly shown to stimulate NADPH oxidation with the highest activity observed with GST M1-1. Using recombinant GSTs the activity of GSTs with artemisinin was at least two fold higher than the reaction with CDNB. Considering these results, it is possible that GSTs may contribute to the metabolism of artemisinin in the presence of NADPH and GSSG-reductase We propose a model, based on the known reactions of GSTs and sesquiterpenes, in which (1) artemisinin reacts with GSH resulting in oxidised glutathione; (2) the oxidised glutathione is then converted to reduced glutathione via glutathione reductase; and (3) the latter reaction may then result in the depletion of NADPH via GSSG-reductase. The ability of artemisinin to react with GSH in the presence of GST may be responsible for the NADPH utilisation observed in vitro and suggests that cytosolic GSTs are likely to be contributing to metabolism of artemisinin and related drugs in vivo. 相似文献
2.
Inhibition of hemozoin formation in Plasmodium falciparum trophozoite extracts by heme analogs: possible implication in the resistance to malaria conferred by the beta-thalassemia trait.
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BACKGROUND: Human falciparum malaria, caused by the intracellular protozoa Plasmodium falciparum, results in 1-2 million deaths per year. P. falciparum digests host erythrocyte hemoglobin within its food vacuole, resulting in the release of potentially toxic free heme. A parasite-specific heme polymerization activity detoxifies the free heme by cross-linking the heme monomers to form hemozoin or malaria pigment. This biochemical process is the target of the widely successful antimalarial drug chloroquine, which is rapidly losing its effectiveness due to the spread of chloroquine resistance. We have shown that chloroquine resistance is not due to changes in the overall catalytic activity of heme polymerization or its chloroquine sensitivity. Therefore, the heme polymerization activity remains a potential target for novel antimalarials. In this study, we investigated the ability of heme analogs to inhibit heme polymerization and parasite growth in erythrocytes. MATERIALS AND METHODS: Incorporation of radioactive hemin substrate into an insoluble hemozoin pellet was used to determine heme polymerization. Incorporation of radioactive hypoxanthine into the nucleic acid of dividing parasites was used to determine the effects of heme analogs on parasite growth. Microscopic and biochemical measurements were made to determine the extent of heme analog entry into infected erythrocytes. RESULTS: The heme analogs tin protoporphyrin IX (SnPP), zinc protoporphyrin IX (ZnPP), and zinc deuteroporphyrin IX, 2,4 bisglycol (ZnBG) inhibited polymerization at micromolar concentrations (ZnPP << SnPP < ZnBG). However, they did not inhibit parasite growth since they failed to gain access to the site of polymerization, the parasite's food vacuole. Finally, we observed high ZnPP levels in erythrocytes from two patients with beta-thalassemia trait, which may inhibit heme polymerization. CONCLUSIONS: The heme analogs tested were able to inhibit hemozoin formation in Plasmodium falciparum trophozite extracts. The increased ZnPP levels found in thalassemic erythrocytes suggest that these may contribute, at least in part, to the observed antimalarial protection conferred by the beta-thalassemia trait. This finding may lead to the development of new forms of antimalarial therapy. 相似文献
3.
Rohrbach P Sanchez CP Hayton K Friedrich O Patel J Sidhu AB Ferdig MT Fidock DA Lanzer M 《The EMBO journal》2006,25(13):3000-3011
The P-glycoprotein homolog of the human malaria parasite Plasmodium falciparum (Pgh-1) has been implicated in decreased susceptibility to several antimalarial drugs, including quinine, mefloquine and artemisinin. Pgh-1 mainly resides within the parasite's food vacuolar membrane. Here, we describe a surrogate assay for Pgh-1 function based on the subcellular distribution of Fluo-4 acetoxymethylester and its free fluorochrome. We identified two distinct Fluo-4 staining phenotypes: preferential staining of the food vacuole versus a more diffuse staining of the entire parasite. Genetic, positional cloning and pharmacological data causatively link the food vacuolar Fluo-4 phenotype to those Pgh-1 variants that are associated with altered drug responses. On the basis of our data, we propose that Pgh-1 imports solutes, including certain antimalarial drugs, into the parasite's food vacuole. The implications of our findings for drug resistance mechanisms and testing are discussed. 相似文献
4.
Digestion of hemoglobin in the food vacuole of the malaria parasite produces very high quantities of redox active toxic free heme. Hemozoin (beta-hematin) formation is a unique process adopted by Plasmodium sp. to detoxify free heme. Hemozoin formation is a validated target for most of the well-known existing antimalarial drugs and considered to be a suitable target to develop new antimalarials. Here we discuss the possible mechanisms of free heme detoxification in the malaria parasite and the mechanistic details of compounds, which offer antimalarial activity by inhibiting hemozoin formation. The chemical nature of new antimalarial compounds showing antimalarial activity through the inhibition of hemozoin formation has also been incorporated, which may help to design future antimalarials with therapeutic potential against multi-drug resistant malaria. 相似文献
5.
Araújo JQ Carneiro JW de Araujo MT Leite FH Taranto AG 《Bioorganic & medicinal chemistry》2008,16(9):5021-5029
Malaria is an infectious disease caused by the unicellular parasite Plasmodium sp. Currently, the malaria parasite is becoming resistant to the traditional pharmacological alternatives, which are ineffective. Artemisinin is the most recent advance in the chemotherapy of malaria. Since it has been proven that artemisinin may act on intracellular heme, we have undertaken a systematic study of several interactions and arrangements between artemisinin and heme. Density Functional Theory calculations were employed to calculate interaction energies, electronic states, and geometrical arrangements for the complex between the heme group and artemisinin. The results show that the interaction between the heme group and artemisinin at long distances occurs through a complex where the iron atom of the heme group retains its electronic features, leading to a quintet state as the most stable one. However, for interaction at short distances, due to artemisinin reduction by the heme group, the most stable complex has a septet spin state. These results suggest that a thermodynamically favorable interaction between artemisinin and heme may happen. 相似文献
6.
Effects of chloroquine on the feeding mechanism of the intraerythrocytic human malarial parasite Plasmodium falciparum 总被引:5,自引:0,他引:5
Ultrastructural investigations of P. falciparum cultivated in vitro in human erythrocytes revealed new features of the feeding mechanism of the parasite. Mature trophozoites and schizonts take up a portion of the host cytosol by endocytosis which is restricted to cytostomes and which involves the invagination of both parasitophorous and parasite membranes. The resulting endocytic vesicles, surrounded by two concentric membranes, migrate towards the central food vacuole membrane. The external membrane of the endocytic vesicles apposes that of the food vacuole, leading to the internalization of vesicles bounded by a single membrane into the vacuole space where they are rapidly degraded. We conclude from this sequence of events that endocytic vesicles fuse with the food vacuole. Treatment of infected cells with therapeutic concentrations of chloroquine inhibited the last step of the feeding process, i.e. vacuolar degradation. This was manifested by the accumulation within the vacuolar space of intact vesicles bounded by single membranes. The implications of these findings for the antimalarial activity of chloroquine are discussed. 相似文献
7.
Artemisinin, an endoperoxide antimalarial, disrupts the hemoglobin catabolism and heme detoxification systems in malarial parasite. 总被引:11,自引:0,他引:11
A V Pandey B L Tekwani R L Singh V S Chauhan 《The Journal of biological chemistry》1999,274(27):19383-19388
Endoperoxide antimalarials based on the ancient Chinese drug Qinghaosu (artemisinin) are currently our major hope in the fight against drug-resistant malaria. Rational drug design based on artemisinin and its analogues is slow as the mechanism of action of these antimalarials is not clear. Here we report that these drugs, at least in part, exert their effect by interfering with the plasmodial hemoglobin catabolic pathway and inhibition of heme polymerization. In an in vitro experiment we observed inhibition of digestive vacuole proteolytic activity of malarial parasite by artemisinin. These observations were further confirmed by ex vivo experiments showing accumulation of hemoglobin in the parasites treated with artemisinin, suggesting inhibition of hemoglobin degradation. We found artemisinin to be a potent inhibitor of heme polymerization activity mediated by Plasmodium yoelii lysates as well as Plasmodium falciparum histidine-rich protein II. Interaction of artemisinin with the purified malarial hemozoin in vitro resulted in the concentration-dependent breakdown of the malaria pigment. Our results presented here may explain the selective and rapid toxicity of these drugs on mature, hemozoin-containing, stages of malarial parasite. Since artemisinin and its analogues appear to have similar molecular targets as chloroquine despite having different structures, they can potentially bypass the quinoline resistance machinery of the malarial parasite, which causes sublethal accumulation of these drugs in resistant strains. 相似文献
8.
AVNER YAYON RINA TIMBERG SHOSHANA FRIEDMAN HAGAI GINSBURG 《The Journal of eukaryotic microbiology》1984,31(3):367-372
Ultrastructural investigations of P. falciparum cultivated in vitro in human erythrocytes revealed new features of the feeding mechanism of the parasite. Mature trophozoites and schizonts take up a portion of the host cytosol by endocytosis which is restricted to cytostomes and which involves the invagination of both parasitophorous and parasite membranes. The resulting endocytic vesicles, surrounded by two concentric membranes, migrate towards the central food vacuole membrane. The external membrane of the endocytic vesicles apposes that of the food vacuole, leading to the internalization of vesicles bounded by a single membrane into the vacuolar space where they are rapidly degraded. We conclude from this sequence of events that endocytic vesicles fuse with the food vacuole. Treatment of infected cells with therapeutic concentrations of chloroquine inhibited the last step of the feeding process, i.e. vacuolar degradation. This was manifested by the accumulation within the vacuolar space of intact vesicles bounded by single membranes. The implications of these findings for the antimalarial activity of chloroquine are discussed. 相似文献
9.
Ostera G Tokumasu F Oliveira F Sa J Furuya T Teixeira C Dvorak J 《Experimental parasitology》2008,120(1):29-38
Nitric oxide (NO) has diverse biological functions. Numerous studies have documented NO’s biosynthetic pathway in a wide variety of organisms. Little is known, however, about NO production in intraerythrocytic Plasmodium falciparum. Using diaminorhodamine-4-methyl acetoxymethylester (DAR-4M AM), a fluorescent indicator, we obtained direct evidence of NO and NO-derived reactive nitrogen species (RNS) production in intraerythrocytic P. falciparum parasites, as well as in isolated food vacuoles from trophozoite stage parasites. We preliminarily identified two gene sequences that might be implicated in NO synthesis in intraerythrocytic P. falciparum. We showed localization of the protein product of one of these two genes, a molecule that is structurally similar to a plant nitrate reductase, in trophozoite food vacuole membranes. We confirmed previous reports on the antiproliferative effect of NOS (nitric oxide synthase) inhibitors in P. falciparum cultures; however, we did not obtain evidence that NOS inhibitors had the ability to inhibit RNS production or that there is an active NOS in mature forms of the parasite. We concluded that a nitrate reductase activity produce NO and NO-derived RNS in or around the food vacuole in P. falciparum parasites. The food vacuole is a critical parasitic compartment involved in hemoglobin degradation, heme detoxification and a target for antimalarial drug action. Characterization of this relatively unexplored synthetic activity could provide important clues into poorly understood metabolic processes of the malaria parasite. 相似文献
10.
Alberto Martínez Chandima S. K. Rajapakse Becky Naoulou Yasemin Kopkalli Lesley Davenport Roberto A. Sánchez-Delgado 《Journal of biological inorganic chemistry》2008,13(5):703-712
The mechanism of antimalarial action of the ruthenium-chloroquine complex [RuCl(2)(CQ)](2) (1), previously shown by us to be active in vitro against CQ-resistant strains of Plasmodium falciparum and in vivo against P. berghei, has been investigated. The complex is rapidly hydrolyzed in aqueous solution to [RuCl(OH(2))(3)(CQ)](2)[Cl](2), which is probably the active species. This compound binds to hematin in solution and inhibits aggregation to beta-hematin at pH approximately 5 to a slightly lower extent than chloroquine diphosphate; more importantly, the heme aggregation inhibition activity of complex 1 is significantly higher than that of CQ when measured at the interface of n-octanol-aqueous acetate buffer mixtures under acidic conditions modeling the food vacuole of the parasite. Partition coefficient measurements confirmed that complex 1 is considerably more lipophilic than CQ in n-octanol-water mixtures at pH approximately 5. This suggests that the principal target of complex 1 is the heme aggregation process, which has recently been reported to be fast and spontaneous at or near water-lipid interfaces. The enhanced antimalarial activity of complex 1 is thus probably due to a higher effective concentration of the drug at or near the interface compared with that of CQ, which accumulates strongly in the aqueous regions of the vacuole under those conditions. Furthermore, the activity of complex 1 against CQ-resistant strains of P. falciparum is probably related to its greater lipophilicity, in line with previous reports indicating a lowered ability of the mutated transmembrane transporter PfCRT to promote the efflux of highly lipophilic drugs. The metal complex also interacts with DNA by intercalation, to a comparable extent and in a similar manner to uncomplexed CQ and therefore DNA binding does not appear to be an important part of the mechanism of antimalarial action in this case. 相似文献
11.
Molecular docking and 3-D-QSAR studies on the possible antimalarial mechanism of artemisinin analogues 总被引:3,自引:0,他引:3
Cheng F Shen J Luo X Zhu W Gu J Ji R Jiang H Chen K 《Bioorganic & medicinal chemistry》2002,10(9):2883-2891
Artemisinin (Qinghaosu) is a natural constituent found in Artemisia annua L, which is an effective drug against chloroquine-resistant Plasmodium falciparum strains and cerebral malaria. The antimalarial activities of artemisinin and its analogues appear to be mediated by the interactions of the drugs with hemin. In order to understand the antimalarial mechanism and the relationship between the physicochemical properties and the antimalarial activities of artemisinin analogues, we performed molecular docking simulations to probe the interactions of these analogues with hemin, and then performed three-dimensional quantitative structure-activity relationship (3-D-QSAR) studies on the basis of the docking models employing comparative molecular force fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Molecular docking simulations generated probable 'bioactive' conformations of artemisinin analogues and provided a new insight into the antimalarial mechanism. The subsequent partial least squares (PLS) analysis indicates that the calculate binding energies correlate well with the experimental activity values. The CoMFA and CoMSIA models based on the bioactive conformations proved to have good predictive ability and in turn match well with the docking result, which further testified the reliability of the docking model. Combining these results, that is molecular docking and 3-D-QSAR, together, the binding model and activity of new synthesized artemisinin derivatives were well explained. 相似文献
12.
A preliminary study from our laboratory found retinol (vitamin A alcohol) to have in vitro activity against Plasmodium falciparum at concentrations close to those in normal human serum (1-3 microM). To characterize the antimalarial potential of retinol in more detail, the 3D7 and K1 laboratory strains of P. falciparum were maintained in continuous culture and [3H]hypoxanthine incorporation and microscopy were used to assess the effect of retinol against asexual stages of the parasite life-cycle. Losses of retinol and retinol-associated hemolysis were also quantified in the in vitro culture system. There were retinol losses of >50% but no hemolysis was observed with added retinol concentrations up to 100 microM. All stages of parasite development showed comparable sensitivity to retinol including merozoite invasion (range of mean IC50 values 10.1-21.4 microM after adjustment for losses). Retinol pre-treatment of uninfected RBC did not inhibit merozoite invasion. Retinol treatment was associated with increased vacuolization within the parasite food vacuole and evidence of parasite membrane rupture. These appearances were similar to those seen with quinoline and artemisinin compounds. Although these data do not support a role for acute retinol supplementation in the treatment of falciparum malaria, they add to knowledge regarding potential antimalarial therapies and justify assessment of more potent synthetic retinoids and their metabolites. 相似文献
13.
Current status of artemisinin and its derivatives as antimalarial drugs 总被引:21,自引:0,他引:21
Artemisinin is a promising and a potent antimalarial drug, which meets the dual challenge posed by drug-resistant parasites and rapid progression of malarial illness. This review article focuses on the progress achieved during the last years in the production of artemisinin from Artemisia annua. The structure, biosynthesis and analysis of artemisinin and its mode of action are described. The review also focuses on clinical studies, toxicity studies, pharmacokinetics and activity of artemisinin related compounds. The production strategies including organic synthesis, extraction from plants, in vitro cultures and alternative strategies for enhancing the yields are also discussed. 相似文献
14.
Nguyen Tien Huy Kaeko Kamei Takushi Yamamoto Yoshiro Kondo Kenji Kanaori Ryo Takano Kunihiko Tajima Saburo Hara 《The Journal of biological chemistry》2002,277(6):4152-4158
Two recent studies have demonstrated that clotrimazole, a potent antifungal agent, inhibits the growth of chloroquine-resistant strains of the malaria parasite, Plasmodium falciparum, in vitro. We explored the mechanism of antimalarial activity of clotrimazole in relation to hemoglobin catabolism in the malaria parasite. Because free heme produced from hemoglobin catabolism is highly toxic to the malaria parasite, the parasite protects itself by polymerizing heme into insoluble nontoxic hemozoin or by decomposing heme coupled to reduced glutathione. We have shown that clotrimazole has a high binding affinity for heme in aqueous 40% dimethyl sulfoxide solution (association equilibrium constant: K(a) = 6.54 x 10(8) m(-2)). Even in water, clotrimazole formed a stable and soluble complex with heme and suppressed its aggregation. The results of optical absorption spectroscopy and electron spin resonance spectroscopy revealed that the heme-clotrimazole complex assumes a ferric low spin state (S = 1/2), having two nitrogenous ligands derived from the imidazole moieties of two clotrimazole molecules. Furthermore, we found that the formation of heme-clotrimazole complexes protects heme from degradation by reduced glutathione, and the complex damages the cell membrane more than free heme. The results described herein indicate that the antimalarial activity of clotrimazole might be due to a disturbance of hemoglobin catabolism in the malaria parasite. 相似文献
15.
为了从原子水平上揭示青蒿素及其类似物的结构与抗疟活性之间的关系,运用密度泛函理论DFT方法,在B3LYP/6-31G*水平上对青蒿素及其类似物二氢青蒿素、蒿甲醚和青蒿琥酯的结构和性质进行了理论计算。从分子的平衡构型、Wiberg键级、溶剂化能、偶极矩和静电势等方面分析了青蒿素及其类似物的抗疟构效关系。结果表明,青蒿素及其类似物结构中七元环上的过氧桥键、醚氧键以及六元环上的内酯结构是其抗疟作用的关键活性位,过氧桥键处负的静电势越多,青蒿素与血红素的相互作用越强,分子的抗疟活性越强。理论预测四个药物分子的抗疟活性顺序为:青蒿素<二氢青蒿素<蒿甲醚<青蒿琥酯,与实验活性结果一致。 相似文献
16.
青蒿素类药物的作用机制:一个长久未决的基础研究挑战 总被引:1,自引:0,他引:1
青蒿素是中国自主研制的抗疟良药,高效、低毒,许多基于青蒿素研发的衍生物具有良好的抗疟效果,近年来已成为抗疟的一线药物,受到世界医疗卫生界的充分肯定.虽然青蒿素结构奇特,抑疟效果显著,但40年来其生物作用机制之谜一直未被彻底破解.针对青蒿素类药物的作用机制,提出了不同的假说,如血红素参与青蒿素的激活并被烷基化从而起到抑疟作用,线粒体参与青蒿素的激活和作用过程,某些特定的蛋白是青蒿素作用靶点等.除抑疟外,青蒿素类药物在杀灭其他种类寄生虫、抑制某些癌症细胞以及抗病毒、治疗类风湿等方面也有一定作用.本文将对青蒿素类药物作用机制的研究进行综述及展望,包括抗疟疾过程中的药物激活、作用靶点以及简要的青蒿素抑制肿瘤细胞作用机制,以期为今后的研究提供帮助. 相似文献
17.
Tangming Peng Shuai Li Linlin Liu Chao Yang Mohd Farhan Ligang Chen Qiaozhu Su Wenhua Zheng 《International journal of biological sciences》2022,18(11):4578
Ischemic stroke is characterized by the presence of both brain ischemic and reperfusion-induced injuries in the brain, leading to neuronal dysfunction and death. Artemisinin, an FDA-approved antimalarial drug, has been reported to have neuroprotective properties. However, the effect of artemisinin on ischemic stroke is not known. In the present study, we investigated the effect of artemisinin on ischemic stroke using an oxygen-glucose deprivation/reperfusion (OGD/RP) cellular model and a mouse middle cerebral artery occlusion (MCAO) animal model and examined the underlying mechanisms. The obtained results revealed that a subclinical antimalarial concentration of artemisinin increased cell viability and decreased LDH release and cell apoptosis. Artemisinin also attenuated the production of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential (Δψm). Importantly, artemisinin attenuated the infarction volume and the brain water content in the MCAO animal model. Artemisinin also improved neurological and behavioural outcomes and restored grasp strength and the recovery of motor function in MCAO animals. Furthermore, artemisinin treatment significantly inhibited the molecular indices of apoptosis, oxidative stress and neuroinflammation and activated the ERK1/2/CREB/BCL-2 signaling pathway. Further validation of the involved signaling pathway by the ERK1/2 inhibitor PD98059 revealed that inhibiting the ERK1/2 signaling pathway or silencing ERK1/2 reversed the neuroprotective effects of artemisinin. These results indicate that artemisinin provides neuroprotection against ischemic stroke via the ERK1/2/CREB/BCL-2 signaling pathway. Our study suggests that artemisinin may play an important role in the prevention and treatment of stroke. 相似文献
18.
Rohrbach P Friedrich O Hentschel J Plattner H Fink RH Lanzer M 《The Journal of biological chemistry》2005,280(30):27960-27969
The acidic food vacuole exerts several important functions during intraerythrocytic development of the human malarial parasite Plasmodium falciparum. Hemoglobin taken up from the host erythrocyte is degraded in the food vacuole, and the heme liberated during this process is crystallized to inert hemozoin. Several anti-malarial drugs target food vacuolar pathways, such as hemoglobin degradation and heme crystallization. Resistance and sensitization to some antimalarials is associated with mutations in food vacuolar membrane proteins. Other studies suggest a role of the food vacuole in ion homeostasis, and release of Ca2+ from the food vacuole may mediate adopted physiological responses. To investigate whether the food vacuole is an intracellular Ca2+ store, which in turn may affect other physiological functions in which this organelle partakes, we have investigated total and exchangeable Ca2+ within the parasite's food vacuole using x-ray microanalysis and quantitative confocal live cell Ca2+ imaging. Apparent free Ca2+ concentrations of approximately 90, approximately 350, and approximately 400 nM were found in the host erythrocyte cytosol, the parasite cytoplasm, and the food vacuole, respectively. In our efforts to determine free intracellular Ca2+ concentrations, we evaluated several Ca2+-sensitive fluorochromes in a live cell confocal setting. We found that the ratiometric Ca2+ indicator Fura-Red provides reliable determinations, whereas measurements using the frequently used Fluo-4 are compromised due to problems arising from phototoxicity, photobleaching, and the strong pH dependence of the dye. Our data suggest that the food vacuole contains only moderate amounts of Ca2+, disfavoring a role as a major intracellular Ca2+ store. 相似文献
19.
20.
In vitro, the heme cofactor of human iron(II) hemoglobin was efficiently and quickly alkylated at meso positions by the peroxide-based antimalarial drug artemisinin, leading to heme-artemisinin-derived covalent adducts. This reaction occurred in the absence of any added protease or in the presence of an excess of an extra non-heme protein, or even when artemisinin was added to hemolysed human blood. This activation of artemisinin by the heme moiety of non-digested hemoglobin clearly indicates the high affinity of this drug for heme, and its efficient alkylating ability under very mild conditions. 相似文献