scholarly journals Reaction of artemisinin with haemoglobin: implications for antimalarial activity

2005 ◽  
Vol 385 (2) ◽  
pp. 409-418 ◽  
Author(s):  
Rangiah KANNAN ◽  
Krishan KUMAR ◽  
Dinkar SAHAL ◽  
Shrikant KUKRETI ◽  
Virander S. CHAUHAN
Keyword(s):  
Ascorbic Acid ◽  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Competitive Inhibition ◽  
Antimalarial Activity ◽  
Food Vacuole ◽  
Primary Target ◽  
Reducing Environment ◽  
Derivatives Of ◽  
Antimalarial Action

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.

scholarly journals Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials

1999 ◽  
Vol 339 (2) ◽  
pp. 363-370 ◽  
Author(s):  
Paul LORIA ◽  
Susanne MILLER ◽  
Michael FOLEY ◽  
Leann TILLEY
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Antimalarial Activity ◽  
Inhibitory Effect ◽  
Food Vacuole ◽  
Equimolar Concentration

The malaria parasite feeds by degrading haemoglobin in an acidic food vacuole, producing free haem moieties as a by-product. The haem in oxyhaemoglobin is oxidized from the Fe(II) state to the Fe(III) state with the consequent production of an equimolar concentration of H2O2. We have analysed the fate of haem molecules in Plasmodium falciparum-infected erythrocytes and have found that only about one third of the haem is polymerized to form haemozoin. The remainder appears to be degraded by a non-enzymic process which leads to an accumulation of iron in the parasite. A possible route for degradation of the haem is by reacting with H2O2, and we show that, under conditions designed to resemble those found in the food vacuole, i.e., at pH 5.2 in the presence of protein, free haem undergoes rapid peroxidative decomposition. Chloroquine and quinacrine are shown to be efficient inhibitors of the peroxidative destruction of haem, while epiquinine, a quinoline compound with very low antimalarial activity, has little inhibitory effect. We also show that chloroquine enhances the association of haem with membranes, while epiquinine inhibits this association, and that treatment of parasitized erythrocytes with chloroquine leads to a build-up of membrane-associated haem in the parasite. We suggest that chloroquine exerts its antimalarial activity by causing a build-up of toxic membrane-associated haem molecules that eventually destroy the integrity of the malaria parasite. We have further shown that resistance-modulating compounds, such as chlorpromazine, interact with haem and efficiently inhibit its degradation. This may explain the weak antimalarial activities of these compounds.

scholarly journals In Vitro Activity of Riboflavin against the Human Malaria Parasite Plasmodium falciparum

2000 ◽  
Vol 44 (1) ◽  
pp. 88-96 ◽  
Author(s):  
Thomas Akompong ◽  
Nafisa Ghori ◽  
Kasturi Haldar
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Antimalarial Activity ◽  
Food Vacuole ◽  
Host Cells ◽  
Asexual Parasite ◽  
Human Malaria Parasite ◽  
Human Malaria ◽  
Average Size

ABSTRACT The human malaria parasite Plasmodium falciparumdigests hemoglobin and polymerizes the released free heme into hemozoin. This activity occurs in an acidic organelle called the food vacuole and is essential for survival of the parasite in erythrocytes. Since acidic conditions are known to enhance the auto-oxidation of hemoglobin, we investigated whether hemoglobin ingested by the parasite was oxidized and whether the oxidation process could be a target for chemotherapy against malaria. We released parasites from their host cells and separately analyzed hemoglobin ingested by the parasites from that remaining in the erythrocytes. Isolated parasites contained elevated amounts (38.5% ± 3.5%) of oxidized hemoglobin (methemoglobin) compared to levels (0.8% ± 0.2%) found in normal, uninfected erythrocytes. Further, treatment of infected cells with the reducing agent riboflavin for 24 h decreased the parasite methemoglobin level by 55%. It also inhibited hemozoin production by 50% and decreased the average size of the food vacuole by 47%. Administration of riboflavin for 48 h resulted in a 65% decrease in food vacuole size and inhibited asexual parasite growth in cultures. High doses of riboflavin are used clinically to treat congenital methemoglobinemia without any adverse side effects. This activity, in conjunction with its impressive antimalarial activity, makes riboflavin attractive as a safe and inexpensive drug for treating malaria caused by P. falciparum.

Food vacuole-associated lipid bodies and heterogeneous lipid environments in the malaria parasite, Plasmodium falciparum

2004 ◽  
Vol 54 (1) ◽  
pp. 109-122 ◽  
Author(s):  
Katherine E. Jackson ◽  
Nectarios Klonis ◽  
David J. P. Ferguson ◽  
Akinola Adisa ◽  
Con Dogovski ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Food Vacuole ◽  
Lipid Bodies ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum

scholarly journals Multiple Antibiotics Exert Delayed Effects against the Plasmodium falciparum Apicoplast

2007 ◽  
Vol 51 (10) ◽  
pp. 3485-3490 ◽  
Author(s):  
Erica L. Dahl ◽  
Philip J. Rosenthal
Keyword(s):  
Plasmodium Falciparum ◽  
Cell Division ◽  
Antimalarial Activity ◽  
Mechanisms Of Action ◽  
Malaria Parasites ◽  
Delayed Effects ◽  
Delayed Death ◽  
Antimalarial Action ◽  
Multiple Antibiotics

ABSTRACT Several classes of antibiotics exert antimalarial activity. The mechanisms of action of antibiotics against malaria parasites have been unclear, and prior studies have led to conflicting results, in part because they studied antibiotics at suprapharmacological concentrations. We examined the antimalarial effects of azithromycin, ciprofloxacin, clindamycin, doxycycline, and rifampin against chloroquine-resistant (W2) and chloroquine-sensitive (3D7) Plasmodium falciparum strains. At clinically relevant concentrations, rifampin killed parasites quickly, preventing them from initiating cell division. In contrast, pharmacological concentrations of azithromycin, ciprofloxacin, clindamycin, and doxycycline were relatively inactive against parasites initially but exerted a delayed death effect, in which the progeny of treated parasites failed to complete erythrocytic development. The drugs that caused delayed death did not alter the distribution of apicoplasts into developing progeny. However, the apicoplasts inherited by the progeny of treated parasites were abnormal. The loss of apicoplast function became apparent as the progeny of antibiotic-treated parasites initiated cell division, with the failure of schizonts to fully mature or for erythrocyte rupture to take place. These findings explain the slow antimalarial action of multiple antibiotics.

scholarly journals Antiplasmodial Activity of [(Aryl)arylsulfanylmethyl]Pyridine

2007 ◽  
Vol 52 (2) ◽  
pp. 705-715 ◽  
Author(s):  
Sanjay Kumar ◽  
Sajal Kumar Das ◽  
Sumanta Dey ◽  
Pallab Maity ◽  
Mithu Guha ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Malaria Parasite ◽  
Spin Trap ◽  
Antimalarial Activity ◽  
Lipid Peroxide ◽  
Food Vacuole ◽  
Mitochondrial Potential ◽  
Free Heme

ABSTRACT A series of [(aryl)arylsufanylmethyl]pyridines (AASMP) have been synthesized. These compounds inhibited hemozoin formation, formed complexes (KD = 12 to 20 μM) with free heme (ferriprotoporphyrin IX) at a pH close to the pH of the parasite food vacuole, and exhibited antimalarial activity in vitro. The inhibition of hemozoin formation may develop oxidative stress in Plasmodium falciparum due to the accumulation of free heme. Interestingly, AASMP developed oxidative stress in the parasite, as evident from the decreased level of glutathione and increased formation of lipid peroxide, H2O2, and hydroxyl radical (·OH) in P. falciparum. AASMP also caused mitochondrial dysfunction by decreasing mitochondrial potential (ΔΨm) in malaria parasite, as measured by both flow cytometry and fluorescence microscopy. Furthermore, the generation of ·OH may be mainly responsible for the antimalarial effect of AASMP since ·OH scavengers such as mannitol, as well as spin trap α-phenyl-n-tertbutylnitrone, significantly protected P. falciparum from AASMP-mediated growth inhibition. Cytotoxicity testing of the active compounds showed selective activity against malaria parasite with selectivity indices greater than 100. AASMP also exhibited profound antimalarial activity in vivo against chloroquine resistant P. yoelii. Thus, AASMP represents a novel class of antimalarial.

scholarly journals Fate of haem iron in the malaria parasite Plasmodium falciparum

2002 ◽  
Vol 365 (2) ◽  
pp. 343-347 ◽  
Author(s):  
Timothy J. EGAN ◽  
Jill M. COMBRINCK ◽  
Joanne EGAN ◽  
Giovanni R. HEARNE ◽  
Helder M. MARQUES ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Chemical Analysis ◽  
Malaria Parasite ◽  
Spectroscopic Imaging ◽  
Food Vacuole ◽  
Electron Spectroscopic Imaging ◽  
Iron Species ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Haem Iron

Chemical analysis has shown that Plasmodium falciparum trophozoites contain 61±2% of the iron within parasitized erythrocytes, of which 92±6% is located within the food vacuole. Of this, 88±9% is in the form of haemozoin. 57Fe-Mössbauer spectroscopy shows that haemozoin is the only detectable iron species in trophozoites. Electron spectroscopic imaging confirms this conclusion.

scholarly journals The Plasmodium falciparum protein PfMRP1 functions as an influx ABC transporter

2022 ◽  
Author(s):  
Miguel Silva ◽  
Carla Calçada ◽  
Nuno Osório ◽  
Vitória Baptista ◽  
Vandana Thathy ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
Plasmodium Falciparum ◽  
Plasma Membrane ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Malaria Parasite ◽  
Drug Transport ◽  
Parasite Species ◽  
Antimalarial Activity ◽  
Falciparum Protein

Abstract Adenosine triphosphate (ATP)-binding cassette (ABC) transporters play an important role in mediating solute or drug transport across cellular membranes. Although this class of transporters has been well characterized in diverse organisms little is known about the physiological roles in Plasmodium falciparum, the deadliest malaria parasite species. We studied the Plasmodium falciparum Multidrug Resistance-associated Protein 1 (PfMRP1; PF3D7_0112200), an ABC transporter localized to the parasite plasma membrane, generating genetic disrupted parasites. We demonstrate that parasites with disrupted pfmrp1 are resistant to folate analogs, methotrexate and aminopterin, with antimalarial activity. This phenotype occurs due to reduction in compound accumulation in the parasite cytoplasm. Phylogenetic analysis supports pfmrp1 being distantly related to ABC transporters in other eukaryotes, suggesting an unusual function. We propose that PfMRP1 can act as a solute importer, a function not previously observed in this organism.

scholarly journals Plants of the Araceae family for malaria and related diseases: a review

2015 ◽  
Vol 17 (4) ◽  
pp. 657-666 ◽  
Author(s):  
G. FRAUSIN ◽  
R. B. S. LIMA ◽  
A. F. HIDALGO ◽  
L. C. MING ◽  
A.M. POHLIT
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Preparation Method ◽  
Antimalarial Activity ◽  
Composition Studies ◽  
In Vitro Growth ◽  
Human Malaria Parasite ◽  
Google Books ◽  
In Vitro Inhibition

ABSTRACTIn the current work we performed a review of the Araceae family species traditionally used to treat malaria and its symptoms. The aim is to reveal the large number of antimalarial Araceae species used worldwide and their great unexplored potential as sources of antimalarial natural products. The SciFinder Scholar, Scielo, PubMed, ScienceDirect and Google books search engines were consulted. Forty-three records of 36 species and 23 genera of Araceae used for malaria and symptoms treatment were found. The neotropical genera Philodendron Schott and Anthurium Schott were the best represented for the use in the treatment of malaria, fevers, liver problems and headaches. Leaves and tubers were the most used parts and decoction was the most common preparation method. The extracts of Araceae species inhibit the in vitro growth of the human malaria parasite, the Plasmodium falciparum Welch, and significant median inhibitory concentrations (IC50) for extracts of guaimbê-sulcado (Rhaphidophora decursiva (Roxb.) Schott), aninga (Montrichardia linifera (Arruda) Schott), Culcasia lancifolia N.E. Br. and forest anchomanes (Anchomanes difformis (Blume) Engl.) have been reported demonstrating the antimalarial and cytotoxicity potential of the extracts and sub-fractions. In the only report about the antimalarial components of this family, the neolignan polysyphorin and the benzoperoxide rhaphidecurperoxin presented strong in vitro inhibition of the D6 and W2 strains of Plasmodiumfalciparum (IC50 = 368-540 ng/mL). No live study about antimalarial activity in animal models has been conducted on a species of Araceae. More bioguided chemical composition studies about the in vitro and also thein vivo antimalarial activity of the Araceae are needed in order to enhance the knowledge about the antimalarial potential of this family.

scholarly journals PfPI3K, a phosphatidylinositol-3 kinase from Plasmodium falciparum, is exported to the host erythrocyte and is involved in hemoglobin trafficking

Blood ◽  
2010 ◽  
Vol 115 (12) ◽  
pp. 2500-2507 ◽  
Author(s):  
Ankush Vaid ◽  
Ravikant Ranjan ◽  
Wynand A. Smythe ◽  
Heinrich C. Hoppe ◽  
Pushkar Sharma
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Second Messengers ◽  
Active Form ◽  
Food Vacuole ◽  
Parasite Growth ◽  
Phosphatidylinositol 3 Kinase ◽  
Pi3k Inhibitors ◽  
Parasite Plasmodium ◽  
Phosphatidylinositol 3

Abstract Polyphosphorylated phosphoinositides (PIPs) are potent second messengers, which trigger a wide variety of signaling and trafficking events in most eukaryotic cells. However, the role and metabolism of PIPs in malaria parasite Plasmodium have remained largely unexplored. Our present studies suggest that PfPI3K, a novel phosphatidylinositol-3-kinase (PI3K) in Plasmodium falciparum, is exported to the host erythrocyte by the parasite in an active form. PfPI3K is a versatile enzyme as it can generate various 3′-phosphorylated PIPs. In the parasite, PfPI3K was localized in vesicular compartments near the membrane and in its food vacuole. PI3K inhibitors wortmannin and LY294002 were effective against PfPI3K and were used to study PfPI3K function. We found that PfPI3K is involved in endocytosis from the host and trafficking of hemoglobin in the parasite. The inhibition of PfPI3K resulted in entrapment of hemoglobin in vesicles in the parasite cytoplasm, which prevented its transport to the food vacuole, the site of hemoglobin catabolism. As a result, hemoglobin digestion, which is a source of amino acids necessary for parasite growth, was attenuated and caused the inhibition of parasite growth.

Sign in / Sign up

Export Citation Format

Share Document