Gametocytocidal Activity of Compounds Against Plasmodium falciparum

2014 ◽  
Vol 04 (03) ◽  
Author(s):  
Ishan Wadi ◽  
Neena Valecha
Keyword(s):  
Plasmodium Falciparum ◽  
Gametocytocidal Activity

scholarly journals Identification of MMV Malaria Box Inhibitors of Plasmodium falciparum Early-Stage Gametocytes Using a Luciferase-Based High-Throughput Assay

2013 ◽  
Vol 57 (12) ◽  
pp. 6050-6062 ◽  
Author(s):  
Leonardo Lucantoni ◽  
Sandra Duffy ◽  
Sophie H. Adjalley ◽  
David A. Fidock ◽  
Vicky M. Avery
Keyword(s):  
Plasmodium Falciparum ◽  
High Throughput ◽  
Early Stage ◽  
Blood Stage ◽  
Stage I ◽  
Mosquito Vector ◽  
Asexual Blood Stage ◽  
Content Type ◽  
Malaria Box ◽  
Gametocytocidal Activity

ABSTRACTThe design of new antimalarial combinations to treatPlasmodium falciparuminfections requires drugs that, in addition to resolving disease symptoms caused by asexual blood stage parasites, can also interrupt transmission to the mosquito vector. Gametocytes, which are essential for transmission, develop as sexual blood stage parasites in the human host over 8 to 12 days and are the most accessible developmental stage for transmission-blocking drugs. Considerable effort is currently being devoted to identifying compounds active against mature gametocytes. However, investigations on the drug sensitivity of developing gametocytes, as well as screening methods for identifying inhibitors of early gametocytogenesis, remain scarce. We have developed a luciferase-based high-throughput screening (HTS) assay using tightly synchronous stage I to III gametocytes from a recombinantP. falciparumline expressing green fluorescent protein (GFP)-luciferase. The assay has been used to evaluate the early-stage gametocytocidal activity of the MMV Malaria Box, a collection of 400 compounds with known antimalarial (asexual blood stage) activity. Screening this collection against early-stage (I to III) gametocytes yielded 64 gametocytocidal compounds with 50% inhibitory concentrations (IC50s) below 2.5 μM. This assay is reproducible and suitable for the screening of large compound libraries, with an average percent coefficient of variance (%CV) of ≤5%, an average signal-to-noise ratio (S:N) of >30, and a Z′ of ∼0.8. Our findings highlight the need for screening efforts directed specifically against early gametocytogenesis and indicate the importance of experimental verification of early-stage gametocytocidal activity in the development of new antimalarial candidates for combination therapy.

Gametocytocidal activity of pyronaridine and DNA topoisomerase II inhibitors against multidrug-resistant Plasmodium falciparum in vitro

2000 ◽  
Vol 48 (4) ◽  
pp. 275-280 ◽  
Author(s):  
Porntip Chavalitshewinkoon-Petmitr ◽  
Ganokwan Pongvilairat ◽  
Saranya Auparakkitanon ◽  
Prapon Wilairat
Keyword(s):  
Plasmodium Falciparum ◽  
Topoisomerase Ii ◽  
Multidrug Resistant ◽  
Dna Topoisomerase Ii ◽  
Dna Topoisomerase ◽  
Topoisomerase Ii Inhibitors ◽  
Gametocytocidal Activity

scholarly journals Potent Plasmodium falciparum Gametocytocidal Activity of Diaminonaphthoquinones, Lead Antimalarial Chemotypes Identified in an Antimalarial Compound Screen

2014 ◽  
Vol 59 (3) ◽  
pp. 1389-1397 ◽  
Author(s):  
Takeshi Q Tanaka ◽  
W. Armand Guiguemde ◽  
David S. Barnett ◽  
Maxim I. Maron ◽  
Jaeki Min ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Late Stage ◽  
Parasite Clearance ◽  
Asexual Parasite ◽  
Content Type ◽  
Drug Candidates ◽  
Control Programs ◽  
Parasite Stage ◽  
Asymptomatic Individuals ◽  
Gametocytocidal Activity

ABSTRACTForty percent of the world's population is threatened by malaria, which is caused byPlasmodiumparasites and results in an estimated 200 million clinical cases and 650,000 deaths each year. Drug resistance has been reported for all commonly used antimalarials and has prompted screens to identify new drug candidates. However, many of these new candidates have not been evaluated against the parasite stage responsible for transmission, gametocytes. IfPlasmodium falciparumgametocytes are not eliminated, patients continue to spread malaria for weeks after asexual parasite clearance. Asymptomatic individuals can also harbor gametocyte burdens sufficient for transmission, and a safe, effective gametocytocidal agent could also be used in community-wide malaria control programs. Here, we identify 15 small molecules with nanomolar activity against late-stage gametocytes. Fourteen are diaminonaphthoquinones (DANQs), and one is a 2-imino-benzo[d]imidazole (IBI). One of the DANQs identified, SJ000030570, is a lead antimalarial candidate. In contrast, 94% of the 650 compounds tested are inactive against late-stage gametocytes. Consistent with the ineffectiveness of most approved antimalarials against gametocytes, of the 19 novel compounds with activity against known anti-asexual-stage targets, only 3 had any strong effect on gametocyte viability. These data demonstrate the distinct biology of the transmission stages and emphasize the importance of screening for gametocytocidal activity. The potent gametocytocidal activity of DANQ and IBI coupled with their efficacy against asexual parasites provides leads for the development of antimalarials with the potential to prevent both the symptoms and the spread of malaria.

scholarly journals A Metabolomic Investigation of the Effect of Eosin B on Gameto-cyte of Plasmodium falciparum using 1HNMR Spectroscopy

2019 ◽  
Author(s):  
Alireza SADEGHI TAFRESHI ◽  
Zahra ZAMANI ◽  
Marjan SABBAGHIAN ◽  
Ramezan Ali KHAVARI-NEJAD ◽  
Mohammad ARJMAND ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Targets ◽  
Culture Medium ◽  
Phenylpyruvic Acid ◽  
Eosin B ◽  
Lysine Degradation ◽  
Phenylalanine Metabolism ◽  
1Hnmr Spectroscopy ◽  
Gametocytocidal Activity ◽  
Important Drug

Background: Recently eosin B was shown to have an effect on the asexual stage of Plasmodium falciparum and in this study, its activity against gametocytes and changes in the culture medium metabolites were investigated using an1HNMR-based metabolomics approach. Methods: In the Biochemistry Department of Pasteur Institute of Iran in 2017, parasites were cultured and gametocytogenesis induced by heparin and 5% hematocrit. Sexual stage parasites were tested by eosin B in 90 well plates and IC50 determined using Lactate Dehydrogenase assay. Gametocytes were treated by IC50 dose of eosin B and the medium collected in the two groups: with eosin B and controls and sent for 1HNMR spectroscopy. The spectra were analyzed on MATLAB interface and the altered metabolites in the culture medium and eosin-affected biochemical pathways were identified by Human Metabolome Database and Metaboanalyst website. Results: The results revealed eosin B had an effective gametocytocidal activity against P. falciparum. The significant metabolites changed in the medium were thiamine, Asp, Asn, Tyr, Lys, Ala, Phenylpyruvic acid, NAD+ and lipids. The main pathways identified were aminoacyl-tRNA biosynthesis, Phenylalanine, tyrosine and tryptophan biosynthesis, Alanine, aspartate and glutamate metabolism, Phenylalanine metabolism, Nicotinate and nicotinamide metabolism, and lysine degradation. Conclusion: Eosin B exhibited substantial gametocytocidal activity and affected important drug targets in the Plasmodium.

scholarly journals Gametocytocidal Activity and Synergistic Interactions of Riboflavin with Standard Antimalarial Drugs against Growth of Plasmodium falciparum In Vitro

2000 ◽  
Vol 44 (11) ◽  
pp. 3107-3111 ◽  
Author(s):  
Thomas Akompong ◽  
Saliha Eksi ◽  
Kim Williamson ◽  
Kasturi Haldar
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Drugs ◽  
Inborn Errors ◽  
Asexual Stage ◽  
Adverse Side Effects ◽  
Synergistic Interactions ◽  
High Doses ◽  
Late Stages ◽  
Gametocytocidal Activity

ABSTRACT Our previous studies have shown that riboflavin has activity against Plasmodium falciparum asexual-stage parasites in vitro. In the present study we examine the gametocytocidal activity of riboflavin and the interaction of riboflavin with some commonly used antimalarial drugs against the asexual forms of P. falciparum in vitro. The addition of riboflavin to P. falciparum cultures killed gametocytes at all stages, even those at late stages (III to V), which are not affected by many of the commonly used antimalarials. Combinations of riboflavin with mefloquine, pyrimethamine, and quinine showed a marked potentiation of the activities of these drugs against asexual-stage parasites in vitro. The combination of riboflavin with artemisinin was additive, while that with chloroquine was mildly antagonistic. High doses of riboflavin are used clinically to treat several inborn errors of metabolism with no adverse side effects. Its efficacy in combination with standard antimalarial drugs in treating and preventing the transmission ofP. falciparum malaria can therefore be evaluated in humans.

scholarly journals Antimalarial Asexual Stage-Specific and Gametocytocidal Activities of HIV Protease Inhibitors

2009 ◽  
Vol 54 (3) ◽  
pp. 1334-1337 ◽  
Author(s):  
Christopher L. Peatey ◽  
Katherine T. Andrews ◽  
Nina Eickel ◽  
Timothy MacDonald ◽  
Alice S. Butterworth ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protease Inhibitors ◽  
Antimalarial Activity ◽  
Effective Concentration ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Asexual Stage ◽  
Gametocytocidal Activity

ABSTRACT The stage-specific antimalarial activities of a panel of antiretroviral protease inhibitors (PIs), including two nonpeptidic PIs (tipranavir and darunavir), were tested in vitro against Plasmodium falciparum. While darunavir demonstrated limited antimalarial activity (effective concentration [EC50], >50 μM), tipranavir was active at clinically relevant concentrations (EC50, 12 to 21 μM). Saquinavir, lopinavir, and tipranavir preferentially inhibited the growth of mature asexual-stage parasites (24 h postinvasion). While all of the PIs tested inhibited gametocytogenesis, tipranavir was the only one to exhibit gametocytocidal activity.

scholarly journals IN VITRO GAMETOCYTOCIDAL ACTIVITY OF ARTEMISININ AND ITS DERIVATIVES ON PLASMODIUM FALCIPARUM

1993 ◽  
Vol 46 (1) ◽  
pp. 37-43 ◽  
Author(s):  
Neera MEHRA ◽  
Virendra K. BHASIN
Keyword(s):  
Plasmodium Falciparum ◽  
Gametocytocidal Activity

scholarly journals Artemisinin exposure at the ring or trophozoite stage impacts Plasmodium falciparum sexual conversion differently

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Harvie P Portugaliza ◽  
Shinya Miyazaki ◽  
Fiona JA Geurten ◽  
Christopher Pell ◽  
Anna Rosanas-Urgell ◽  
...  
Keyword(s):  
Public Health ◽  
Plasmodium Falciparum ◽  
Complex Relationship ◽  
Trophozoite Stage ◽  
Fourfold Increase ◽  
Conversion Rates ◽  
Multiplication Cycle ◽  
The Impact ◽  
Gametocytocidal Activity ◽  
Potential Public Health

Malaria transmission is dependent on the formation of gametocytes in the human blood. The sexual conversion rate, the proportion of asexual parasites that convert into gametocytes at each multiplication cycle, is variable and reflects the relative parasite investment between transmission and maintaining the infection. The impact of environmental factors such as drugs on sexual conversion rates is not well understood. We developed a robust assay using gametocyte-reporter parasite lines to accurately measure the impact of drugs on sexual conversion rates, independently from their gametocytocidal activity. We found that exposure to subcurative doses of the frontline antimalarial drug dihydroartemisinin (DHA) at the trophozoite stage resulted in a ~ fourfold increase in sexual conversion. In contrast, no increase was observed when ring stages were exposed or in cultures in which sexual conversion was stimulated by choline depletion. Our results reveal a complex relationship between antimalarial drugs and sexual conversion, with potential public health implications.

Ultrastructural observations on the in vitro cytoadherence of Plasmodium falciparum infected red blood cells

1990 ◽  
Vol 48 (3) ◽  
pp. 914-915
Author(s):  
D.J.P. Ferguson ◽  
A.R. Berendt ◽  
J. Tansey ◽  
K. Marsh ◽  
C.I. Newbold
Keyword(s):  
Plasmodium Falciparum ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Umbilical Vein ◽  
Cell Types ◽  
Amelanotic Melanoma ◽  
Cytoplasmic Process ◽  
Umbilical Vein Endothelial Cells

In human malaria, the most serious clinical manifestation is cerebral malaria (CM) due to infection with Plasmodium falciparum. The pathology of CM is thought to relate to the fact that red blood cells containing mature forms of the parasite (PRBC) cytoadhere or sequester to post capillary venules of various tissues including the brain. This in vivo phenomenon has been studied in vitro by examining the cytoadherence of PRBCs to various cell types and purified proteins. To date, three Ijiost receptor molecules have been identified; CD36, ICAM-1 and thrombospondin. The specific changes in the PRBC membrane which mediate cytoadherence are less well understood, but they include the sub-membranous deposition of electron-dense material resulting in surface deformations called knobs. Knobs were thought to be essential for cytoadherence, lput recent work has shown that certain knob-negative (K-) lines can cytoadhere. In the present study, we have used electron microscopy to re-examine the interactions between K+ PRBCs and both C32 amelanotic melanoma cells and human umbilical vein endothelial cells (HUVEC).We confirm previous data demonstrating that C32 cells possess numerous microvilli which adhere to the PRBC, mainly via the knobs (Fig. 1). In contrast, the HUVEC were relatively smooth and the PRBCs appeared partially flattened onto the cell surface (Fig. 2). Furthermore, many of the PRBCs exhibited an invagination of the limiting membrane in the attachment zone, often containing a cytoplasmic process from the endothelial cell (Fig. 2).

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