scholarly journals Cell Swelling Induced by the Antimalarial KAE609 (Cipargamin) and Other PfATP4-Associated Antimalarials

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Adelaide S. M. Dennis ◽  
Adele M. Lehane ◽  
Melanie C. Ridgway ◽  
John P. Holleran ◽  
Kiaran Kirk
Keyword(s):  
Malaria Parasite ◽  
Antimalarial Activity ◽  
External Environment ◽  
Osmotic Fragility ◽  
Cell Swelling ◽  
Efflux Transporter ◽  
Extracellular Medium ◽  
Human Malaria Parasite ◽  
Content Type ◽  
Antimalarial Agents

ABSTRACTFor an increasing number of antimalarial agents identified in high-throughput phenotypic screens, there is evidence that they target PfATP4, a putative Na+efflux transporter on the plasma membrane of the human malaria parasitePlasmodium falciparum. For several such “PfATP4-associated” compounds, it has been noted that their addition to parasitized erythrocytes results in cell swelling. Here we show that six structurally diverse PfATP4-associated compounds, including the clinical candidate KAE609 (cipargamin), induce swelling of both isolated blood-stage parasites and intact parasitized erythrocytes. The swelling of isolated parasites is dependent on the presence of Na+in the external environment and may be attributed to the osmotic consequences of Na+uptake. The swelling of the parasitized erythrocyte results in an increase in its osmotic fragility. Countering cell swelling by increasing the osmolarity of the extracellular medium reduces the antiplasmodial efficacy of PfATP4-associated compounds, consistent with cell swelling playing a role in the antimalarial activity of this class of compounds.

scholarly journals Artemisone and Artemiside Are Potent Panreactive Antimalarial Agents That Also Synergize Redox Imbalance in Plasmodium falciparum Transmissible Gametocyte Stages

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Dina Coertzen ◽  
Janette Reader ◽  
Mariëtte van der Watt ◽  
Sindisiwe H. Nondaba ◽  
Liezl Gibhard ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Control ◽  
Malaria Parasite ◽  
Redox Homeostasis ◽  
New Drugs ◽  
Content Type ◽  
Artemisinin Derivatives ◽  
Antimalarial Agents ◽  
Redox Partner ◽  
Emergence Of Resistance

ABSTRACT The emergence of resistance toward artemisinin combination therapies (ACTs) by the malaria parasite Plasmodium falciparum has the potential to severely compromise malaria control. Therefore, the development of new artemisinins in combination with new drugs that impart activities toward both intraerythrocytic proliferative asexual and transmissible gametocyte stages, in particular, those of resistant parasites, is urgently required. We define artemisinins as oxidant drugs through their ability to oxidize reduced flavin cofactors of flavin disulfide reductases critical for maintaining redox homeostasis in the malaria parasite. Here we compare the activities of 10-amino artemisinin derivatives toward the asexual and gametocyte stages of P. falciparum parasites. Of these, artemisone and artemiside inhibited asexual and gametocyte stages, particularly stage V gametocytes, in the low-nanomolar range. Further, treatment of both early and late gametocyte stages with artemisone or artemiside combined with the pro-oxidant redox partner methylene blue displayed notable synergism. These data suggest that modulation of redox homeostasis is likely an important druggable process, particularly in gametocytes, and this finding thereby enhances the prospect of using combinations of oxidant and redox drugs for malaria control.

scholarly journals Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Hangjun Ke ◽  
Joanne M. Morrisey ◽  
Shiwei Qu ◽  
Oraphin Chantarasriwong ◽  
Michael W. Mather ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Morphological Changes ◽  
Biological Activities ◽  
Hek293 Cells ◽  
Therapeutic Window ◽  
Malaria Parasites ◽  
Content Type ◽  
Lead Compounds ◽  
Antimalarial Agents ◽  
Transport Chain

ABSTRACT Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia. CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ∼10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents.

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 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.

scholarly journals Radicicol-Mediated Inhibition of Topoisomerase VIB-VIA Activity of the Human Malaria Parasite Plasmodium falciparum

mSphere ◽  
2016 ◽  
Vol 1 (1) ◽  
Author(s):  
Sureshkumar Chalapareddy ◽  
Swati Chakrabarty ◽  
Mrinal Kanti Bhattacharyya ◽  
Sunanda Bhattacharyya
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Complex ◽  
Malaria Parasite ◽  
Specific Inhibitor ◽  
Assay System ◽  
Biochemical Assay ◽  
Dependent Manner ◽  
Human Malaria Parasite ◽  
Content Type ◽  
Human Malaria

ABSTRACT In this study we characterize topoisomerase VI from Plasmodium falciparum using genetic and biochemical approaches. We use various inhibitors and identify radicicol as a specific inhibitor of its decatenation activity. We establish a very simple and economical biochemical assay system that can be exploited to screen inhibitors of PfTopoVI. Plasmodium falciparum topoisomerase VIB (TopoVIB)-TopoVIA (TopoVIB-VIA) complex can be potentially exploited as a drug target against malaria due to its absence from the human genome. Previous work in our laboratory has suggested that P. falciparum TopoVIB (PfTopoVIB) might be a target of radicicol since treatment of parasite cultures with this antibiotic is associated with upregulation of Plasmodium TopoVIB at the transcript level as well as at the protein level. Further studies demonstrated that radicicol treatment impaired mitochondrial replication of human malaria parasite P. falciparum. However, the technical challenge associated with the expression of the above protein complex hampered its functional characterization. Using Saccharomyces cerevisiae as a heterologous system, we expressed PfTopoVIB (Myc-tagged) and PfTopoVIA (Flag-tagged) (PfTopoVIB-VIA) proteins. Yeast two-hybrid analysis showed the formation of PfTopoVIB homodimers and PfTopoVIB/PfTopoVIA heteromers. Our study demonstrated that PfTopoVIB and PfTopoVIA together can rescue the lethal phenotype of yeast ΔtopoII mutants, whereas Plasmodium topoisomerase VIB alone cannot. Using yeast cell-free extracts harboring the PfTopoVIB-VIA protein complex, we have performed a decatenation assay and observed that PfTopoVIB-VIA can decatenate DNA in an ATP- and Mg2+-dependent manner. The specificity of this enzyme is established by abrogation of its activity in the presence of PfTopoVIB-specific antibody. Our study results show that radicicol and etoposide can specifically inhibit PfTopoVIB-VIA decatenation activity whereas the gyrase inhibitor novobiocin cannot. Such a yeast-based assay system can be employed in screening specific inhibitors against Plasmodium VIB-VIA. IMPORTANCE In this study we characterize topoisomerase VI from Plasmodium falciparum using genetic and biochemical approaches. We use various inhibitors and identify radicicol as a specific inhibitor of its decatenation activity. We establish a very simple and economical biochemical assay system that can be exploited to screen inhibitors of PfTopoVI.

scholarly journals Anthracene-Polyamine Conjugates InhibitIn VitroProliferation of Intraerythrocytic Plasmodium falciparum Parasites

2013 ◽  
Vol 57 (6) ◽  
pp. 2874-2877 ◽  
Author(s):  
Jandeli Niemand ◽  
Pieter Burger ◽  
Bianca K. Verlinden ◽  
Janette Reader ◽  
Annie M. Joubert ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Plasmodium Falciparum ◽  
Malaria Parasite ◽  
Human Malaria Parasite ◽  
Content Type ◽  
Human Malaria ◽  
Parasite Cell ◽  
Polyamine Conjugates

ABSTRACTAnthracene-polyamine conjugates inhibit thein vitroproliferation of the intraerythrocytic human malaria parasitePlasmodium falciparum, with 50% inhibitory concentrations (IC50s) in the nM to μM range. The compounds are taken up into the intraerythrocytic parasite, where they arrest the parasite cell cycle. Both the anthracene and polyamine components of the conjugates play a role in their antiplasmodial effect.

scholarly journals Antimalarial Activity of Tulathromycin in a Murine Model of Malaria

2015 ◽  
Vol 59 (6) ◽  
pp. 3672-3674 ◽  
Author(s):  
Nicolas Villarino ◽  
Joshua E. Denny ◽  
Nathan W. Schmidt
Keyword(s):  
Murine Model ◽  
Antimalarial Activity ◽  
Parasite Burden ◽  
Plasmodium Yoelii ◽  
Content Type ◽  
Antimalarial Agents ◽  
Progression Of Disease ◽  
Time Of Infection ◽  
And Control

ABSTRACTThere is an urgent need for new antimalarial agents and strategies to treat and control malaria. This study shows an antiplasmodium effect of tulathromycin in mice infected withPlasmodium yoelii. The administration of tulathromycin around the time of infection prevented the progression of disease in 100% of the animals. In addition, highly parasitized mice treated with tulathromycin showed a decreased parasite burden and cleared the parasite faster than did untreated infected mice.

scholarly journals In Vivo Antimalarial Activity of the Beta-Carboline Alkaloid Manzamine A

2000 ◽  
Vol 44 (6) ◽  
pp. 1645-1649 ◽  
Author(s):  
Kenny K. H. Ang ◽  
Michael J. Holmes ◽  
Tatsuo Higa ◽  
Mark T. Hamann ◽  
Ursula A. K. Kara
Keyword(s):  
Plasmodium Berghei ◽  
Malaria Parasite ◽  
Antimalarial Activity ◽  
Single Injection ◽  
Morphological Changes ◽  
Rodent Malaria Parasite ◽  
Manzamine A ◽  
Antimalarial Agents ◽  
Single Intraperitoneal Injection

ABSTRACT Manzamine A, a β-carboline alkaloid present in several marine sponge species, inhibits the growth of the rodent malaria parasitePlasmodium berghei in vivo. More than 90% of the asexual erythrocytic stages of P. berghei were inhibited after a single intraperitoneal injection of manzamine A into infected mice. A remarkable aspect of manzamine A treatment is its ability to prolong the survival of highly parasitemic mice, with 40% recovery 60 days after a single injection. Oral administration of an oil suspension of manzamine A also produced significant reductions in parasitemia. The plasma manzamine A concentration peaked 4 h after injection and remained high even at 48 h. Morphological changes of P. berghei were observed 1 h after treatment of infected mice. (−)-8-Hydroxymanzamine A also displayed antimalarial activity, whereas manzamine F, a ketone analog of manzamine A, did not. Our results suggest that manzamine A and (−)-8-hydroxymanzamine A are promising new antimalarial agents.

scholarly journals Phosphorylation of Rhoptry Protein RhopH3 Is Critical for Host Cell Invasion by the Malaria Parasite

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Roseleen Ekka ◽  
Ankit Gupta ◽  
Sonika Bhatnagar ◽  
Pawan Malhotra ◽  
Pushkar Sharma
Keyword(s):  
Host Cell ◽  
Cell Invasion ◽  
Blood Cells ◽  
Malaria Infection ◽  
Malaria Parasite ◽  
Host Cell Invasion ◽  
Human Malaria Parasite ◽  
Content Type ◽  
Rhoptry Protein

ABSTRACT Merozoites formed after asexual division of the malaria parasite invade the host red blood cells (RBCs), which is critical for initiating malaria infection. The process of invasion involves specialized organelles like micronemes and rhoptries that discharge key proteins involved in interaction with host RBC receptors. RhopH complex comprises at least three proteins, which include RhopH3. RhopH3 is critical for the process of red blood cell (RBC) invasion as well as intraerythrocytic development of human malaria parasite Plasmodium falciparum. It is phosphorylated at serine 804 (S804) in the parasite; however, it is unclear if phosphorylation regulates its function. To address this, a CRISPR-CAS9-based approach was used to mutate S804 to alanine (A) in P. falciparum. Using this phosphomutant (R3_S804A) of RhopH3, we demonstrate that the phosphorylation of S804 is critical for host RBC invasion by the parasite but not for its intraerythrocytic development. Importantly, the phosphorylation of RhopH3 regulates its localization to the rhoptries and discharge from the parasite, which is critical for RBC invasion. We also identified P. falciparum CDPK1 (PfCDPK1) as a possible candidate kinase for RhopH3-S804 phosphorylation and found that it regulates RhopH3 secretion from the parasite. These findings provide novel insights into the role of phosphorylation in rhoptry release and invasion, which is poorly understood. IMPORTANCE Host cell invasion by the malaria parasite is critical for establishing infection in human host and is dependent on discharge of key ligands from organelles like rhoptry and microneme, and these ligands interact with host RBC receptors. In the present study, we demonstrate that phosphorylation of a key rhoptry protein, RhopH3, is critical for host invasion. Phosphorylation regulates its localization to rhoptries and discharge from the parasite.

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