The Effects of Polyamine Analogues on Malaria Parasites In Vitro and In Vivo

1988 ◽  
pp. 717-726 ◽  
Author(s):  
Alan J. Bitonti ◽  
Peter P. McCann ◽  
Albert Sjoerdsma
Keyword(s):  
Malaria Parasites ◽  
Polyamine Analogues

scholarly journals Ex VivoMaturation Assay for Testing Antimalarial Sensitivity of Rodent Malaria Parasites

2016 ◽  
Vol 60 (11) ◽  
pp. 6859-6866 ◽  
Author(s):  
Zi Wei Chang ◽  
Benoit Malleret ◽  
Bruce Russell ◽  
Laurent Rénia ◽  
Carla Claser
Keyword(s):  
Ex Vivo ◽  
Single Step ◽  
Parasite Development ◽  
Ring Stage ◽  
Malaria Parasites ◽  
Rodent Malaria ◽  
Content Type ◽  
Parasite Biology

ABSTRACTEx vivoassay systems provide a powerful approach to studying human malaria parasite biology and to testing antimalarials. For rodent malaria parasites, short-termin vitroculture andex vivoantimalarial susceptibility assays are relatively cumbersome, relying onin vivopassage for synchronization, since ring-stage parasites are an essential starting material. Here, we describe a new approach based on the enrichment of ring-stagePlasmodium berghei,P. yoelii, andP. vinckei vinckeiusing a single-step Percoll gradient. Importantly, we demonstrate that the enriched ring-stage parasites develop synchronously regardless of the parasite strain or species used. Using a flow cytometry assay with Hoechst and ethidium or MitoTracker dye, we show that parasite development is easily and rapidly monitored. Finally, we demonstrate that this approach can be used to screen antimalarial drugs.

scholarly journals Mammalian deubiquitinating enzyme inhibitors display in vitro and in vivo activity against malaria parasites and potentiate artemisinin action

2020 ◽  
Author(s):  
Nelson V. Simwela ◽  
Katie R. Hughes ◽  
Michael T. Rennie ◽  
Michael P. Barrett ◽  
Andrew P. Waters
Keyword(s):  
Anticancer Agents ◽  
Drug Targets ◽  
Reverse Genetics ◽  
Enzyme Inhibitors ◽  
Artemisinin Resistance ◽  
Drug Repurposing ◽  
Antimalarial Drugs ◽  
Malaria Parasites

AbstractCurrent malaria control efforts rely significantly on artemisinin combinational therapies which have played massive roles in alleviating the global burden of the disease. Emergence of resistance to artemisinins is therefore, not just alarming but requires immediate intervention points such as development of new antimalarial drugs or improvement of the current drugs through adjuvant or combination therapies. Artemisinin resistance is primarily conferred by Kelch13 propeller mutations which are phenotypically characterised by generalised growth quiescence, altered haemoglobin trafficking and downstream enhanced activity of the parasite stress pathways through the ubiquitin proteasome system (UPS). Previous work on artemisinin resistance selection in a rodent model of malaria, which we and others have recently validated using reverse genetics, has also shown that mutations in deubiquitinating enzymes, DUBs (upstream UPS component) modulates susceptibility of malaria parasites to both artemisinin and chloroquine. The UPS or upstream protein trafficking pathways have, therefore, been proposed to be not just potential drug targets, but also possible intervention points to overcome artemisinin resistance. Here we report the activity of small molecule inhibitors targeting mammalian DUBs in malaria parasites. We show that generic DUB inhibitors can block intraerythrocytic development of malaria parasites in vitro and possess antiparasitic activity in vivo and can be used in combination with additive effect. We also show that inhibition of these upstream components of the UPS can potentiate the activity of artemisinin in vitro as well as in vivo to the extent that ART resistance can be overcome. Combinations of DUB inhibitors anticipated to target different DUB activities and downstream 20s proteasome inhibitors are even more effective at improving the potency of artemisinins than either inhibitors alone providing proof that targeting multiple UPS activities simultaneously could be an attractive approach to overcoming artemisinin resistance. These data further validate the parasite UPS as a target to both enhance artemisinin action and potentially overcome resistance. Lastly, we confirm that DUB inhibitors can be developed into in vivo antimalarial drugs with promise for activity against all of human malaria and could thus further exploit their current pursuit as anticancer agents in rapid drug repurposing programs.Graphical abstract

Synergy of the antiretroviral protease inhibitor indinavir and chloroquine against malaria parasites in vitro and in vivo

2011 ◽  
Vol 109 (6) ◽  
pp. 1519-1524 ◽  
Author(s):  
Xiaofen Li ◽  
Zhengxiang He ◽  
Lili Chen ◽  
Yayong Li ◽  
Qinyan Li ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Malaria Parasites

In vitro and in vivo antimalarial activity of ferrochloroquine, a ferrocenyl analogue of chloroquine against chloroquine-resistant malaria parasites

2001 ◽  
Vol 87 (3) ◽  
pp. 239-244 ◽  
Author(s):  
L. Delhaes ◽  
H. Abessolo ◽  
L. Berry ◽  
P. Delcourt ◽  
L. Maciejewski ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Malaria Parasites

scholarly journals Synthesis and Evaluation of Chirally Defined Side Chain Variants of 7-Chloro-4-Aminoquinoline To Overcome Drug Resistance in Malaria Chemotherapy

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
Vasantha Rao Dola ◽  
Awakash Soni ◽  
Pooja Agarwal ◽  
Hafsa Ahmad ◽  
Kanumuri Siva Rama Raju ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Solid State ◽  
Side Chain ◽  
Detailed Structure ◽  
Preclinical Development ◽  
Malaria Parasites ◽  
Sar Studies ◽  
Structure Activity

ABSTRACT A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methylpiperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.

scholarly journals Aspidosperma (Apocynaceae) plant cytotoxicity and activity towards malaria parasites. Part II: experimental studies withAspidosperma ramiflorum in vivo and in vitro

2015 ◽  
Vol 110 (7) ◽  
pp. 906-913 ◽  
Author(s):  
Anna CC Aguiar ◽  
Ananda C Cunha ◽  
Isabela Penna Ceravolo ◽  
Regina A Correia Gonçalves ◽  
Arildo JB Oliveira ◽  
...  
Keyword(s):  
Experimental Studies ◽  
Malaria Parasites

scholarly journals Disruption of the coordination between host circadian rhythms and malaria parasite development alters the duration of the intraerythrocytic cycle

2019 ◽  
Author(s):  
Amit K. Subudhi ◽  
Aidan J. O’Donnell ◽  
Abhinay Ramaprasad ◽  
Hussein M. Abkallo ◽  
Abhinav Kaushik ◽  
...  
Keyword(s):  
Parasite Development ◽  
Developmental Cycle ◽  
Plasmodium Chabaudi ◽  
Malaria Parasites ◽  
Multiple Processes ◽  
Free Running ◽  
Fitness Benefits ◽  
Circadian Transcription

Malaria parasites complete their intra-erythrocytic developmental cycle (IDC) in multiples of 24 hours (depending on the species), suggesting a circadian basis to the asexual cell cycle, but the mechanism controlling this periodicity is unknown. Combining in vivo and in vitro approaches using rodent and human malaria parasites, we reveal that: (i) 57% of Plasmodium chabaudi genes exhibit 24 h “circadian” periodicity in transcription; (ii) 58% of these genes lose transcriptional rhythmicity when the IDC is out-of-synchrony with host rhythms; (iii) 9% of Plasmodium falciparum genes show circadian transcription under free-running conditions; (iv) Serpentine receptor 10 (SR10) has a circadian transcription profile and disrupting it in rodent malaria parasites shortens the IDC by 2-3 hours; (v) Multiple processes including DNA replication and the ubiquitin and proteasome pathways are affected by loss of coordination with host rhythms and by disruption of SR10. Our results show that malaria parasites are at least partly responsible for scheduling their IDCs explaining the fitness benefits of coordination with host rhythms.

scholarly journals Rapid inducible protein displacement in Plasmodium in vivo and in vitro using knocksideways technology

2017 ◽  
Vol 2 ◽  
pp. 18 ◽  
Author(s):  
Katie R. Hughes ◽  
Andy P. Waters
Keyword(s):  
Plasmodium Berghei ◽  
Genetic Manipulation ◽  
Live Imaging ◽  
Malaria Parasites ◽  
Essential Proteins ◽  
Inducible Protein ◽  
Fluorescent Tags ◽  
Proof Of Principle

A deeper understanding of the biology of the Plasmodium parasite is essential in order to identify targets for interventions, with the ultimate aim of eliminating malaria. Determining the function(s) of essential proteins in Plasmodium has, until recently, been hampered by the lack of efficient conditional systems to abrogate proteins. We report the adaptation of a conditional technology, knocksideways (KS), for use in Plasmodium berghei, which can potentially rapidly inactivate proteins of interest through relocalisation. The system is induced using rapamycin, which allows for KS both in vitro and in vivo and is effective more rapidly than any other reported system. KS utilises pairs of fluorescent tags that facilitate live imaging and allows for rapid confirmation of efficient protein redistribution on live parasites, allowing for streamlined workflows. We demonstrate the characteristics of the system using transgenically expressed cytoplasmic GFP and provide proof of principle by inducibly redistributing a number of proteins with different native, subcellular locations.  We also demonstrate that KS can be applied to both mammalian and insect stages of Plasmodium. KS expands the range of (conditional) technologies for genetic manipulation of malaria parasites and offers the potential to be further developed for medium throughput phenotype screens.

Farnesyltransferase Inhibitors Inhibit the Growth of Malaria Parasites In Vitro and In Vivo

2004 ◽  
Vol 43 (2) ◽  
pp. 251-254 ◽  
Author(s):  
Jochen Wiesner ◽  
Katja Kettler ◽  
Jacek Sakowski ◽  
Regina Ortmann ◽  
Alejandro M. Katzin ◽  
...  
Keyword(s):  
Farnesyltransferase Inhibitors ◽  
Malaria Parasites

scholarly journals Design and Activity of Antimicrobial Peptides against Sporogonic-Stage Parasites Causing Murine Malarias

2002 ◽  
Vol 46 (7) ◽  
pp. 2104-2110 ◽  
Author(s):  
Romanico B. G. Arrighi ◽  
Chikashi Nakamura ◽  
Jun Miyake ◽  
Hilary Hurd ◽  
J. Grant Burgess
Keyword(s):  
Intensity Of Infection ◽  
Malaria Parasites ◽  
Sporogonic Stage ◽  
Short Novel ◽  
Large Numbers ◽  
Level Of Activity ◽  
Parasite Stage ◽  
Pathogenic Microbes

ABSTRACT Insects produce several types of peptides to combat a broad spectrum of invasive pathogenic microbes, including protozoans. However, despite this defense response, infections are often established. Our aim was to design novel peptides that produce high rates of mortality among protozoa of the genus Plasmodium, the malaria parasites. Using existing antimicrobial peptide sequences as templates, we designed and synthesized three short novel hybrids, designated Vida1 to Vida3. Each has a slightly different predicted secondary structure. The peptides were tested against sporogonic stages of the rodent malaria parasites Plasmodium berghei (in vitro and in vivo) and P. yoelii nigeriensis (in vitro). The level of activity varied for each peptide and according to the parasite stage targeted. Vida3 (which is predicted to have large numbers of β sheets and coils but no α helices) showed the highest level of activity, killing the early sporogonic stages in culture and causing highly significant reductions in the prevalence and intensity of infection of P. berghei after oral administration or injection in Anopheles gambiae mosquitoes. The secondary structures of these peptides may play a crucial role in their ability to interact with and kill sporogonic forms of the malaria parasite.

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