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Sub-cellular Biochemistry 2008
Review
Topics: Animals; Erythrocytes; Host-Parasite Interactions; Humans; Ligands; Models, Biological; Phenotype; Plasmodium falciparum; Protozoan Proteins; Receptors, Cell Surface
PubMed: 18512340
DOI: 10.1007/978-0-387-78267-6_3 -
Methods in Cell Biology 1994
Review
Topics: Animals; Merozoite Surface Protein 1; Molecular Biology; Parasitology; Plasmodium falciparum; Protein Precursors; Protein Processing, Post-Translational; Protozoan Proteins
PubMed: 7707987
DOI: 10.1016/s0091-679x(08)61853-1 -
Parasitology Jan 2011One of the most important public health problems in the world today is the emergence and dissemination of drug-resistant malaria parasites. Plasmodium falciparum is the... (Review)
Review
One of the most important public health problems in the world today is the emergence and dissemination of drug-resistant malaria parasites. Plasmodium falciparum is the causative agent of the most lethal form of human malaria. New anti-malarial strategies are urgently required, and their design and development require the identification of potential therapeutic targets. However, the molecular mechanisms controlling the life cycle of the malaria parasite are still poorly understood. The published genome sequence of P. falciparum and previous studies have revealed that several homologues of eukaryotic signalling proteins, such as protein kinases, are relatively conserved. Protein kinases are now widely recognized as important drug targets in protozoan parasites. Cyclic AMP-dependent protein kinase (PKA) is implicated in numerous processes in mammalian cells, and the regulatory mechanisms of the cAMP pathway have been characterized. P. falciparum cAMP-dependent protein kinase plays an important role in the parasite's life cycle and thus represents an attractive target for the development of anti-malarial drugs. In this review, we focus on the P. falciparum cAMP/PKA pathway to provide new insights and an improved understanding of this signalling cascade.
Topics: Cyclic AMP-Dependent Protein Kinases; Drug Delivery Systems; Malaria, Falciparum; Plasmodium falciparum; Protozoan Proteins; Signal Transduction
PubMed: 20663247
DOI: 10.1017/S003118201000096X -
Medicinal Research Reviews Sep 2002Malarial parasites remain a health problem of staggering proportions. Worldwide, they infect about 500 million, incapacitate tens of millions, and kill approximately 2.5... (Review)
Review
Malarial parasites remain a health problem of staggering proportions. Worldwide, they infect about 500 million, incapacitate tens of millions, and kill approximately 2.5 million (mostly children) annually. Four species infect humans, but most deaths are caused by one particular species, Plasmodium falciparum. The rising number of malarial deaths is due in part to increased drug resistance in P. falciparum. There are many varieties of antimalarial drug resistance, and there may very well be several molecular level contributions to each variety. This is because there are a number of different drugs with different mechanisms of action in use, and more than one molecular event may sometimes be relevant for resistance to any one class of drugs. Thus, "multidrug" resistance in a clinical setting likely entails complex combinations of overlapping resistance pathways, each specific for one class of drug, that then add together to confer the particular multidrug resistance phenotype. Nonetheless, rapid progress has been made in recent years in elucidating mechanisms of resistance to specific classes of antimalarial drugs. As one example, resistance to the antimalarial drug chloroquine, which has been the mainstay therapy for decades, is becoming well understood. This article focuses on recent advances in determining the molecular mechanism of chloroquine resistance, with particular attention to the biochemistry and biophysics of the P. falciparum digestive vacuole, wherein changes in pH have recently been found to be associated with chloroquine resistance.
Topics: Animals; Antimalarials; Chloroquine; Drug Resistance; Plasmodium falciparum
PubMed: 12210555
DOI: 10.1002/med.10016 -
Amino Acids Feb 2010Inhibition of polyamine biosynthesis and/or the perturbation of polyamine functionality have been exploited with success against parasitic diseases such as Trypanosoma... (Review)
Review
Inhibition of polyamine biosynthesis and/or the perturbation of polyamine functionality have been exploited with success against parasitic diseases such as Trypanosoma infections. However, when the classical polyamine biosynthesis inhibitor, alpha-difluoromethylornithine, is used against the human malaria parasite, Plasmodium falciparum, it results in only a cytostatic growth arrest. Polyamine metabolism in this parasite has unique properties not shared by any other organism. These include the bifunctional arrangement of the catalytic decarboxylases and an apparent absence of the typical polyamine interconversion pathways implying different mechanisms for the regulation of polyamine homeostasis that includes the uptake of exogenous polyamines at least in vitro. These properties make polyamine metabolism an enticing drug target in P. falciparum provided that the physiological and functional consequences of polyamine metabolism perturbation are understood. This review highlights our current understanding of the biological consequences of inhibition of the biosynthetic enzymes in the polyamine pathway in P. falciparum as revealed by several global analytical approaches. Ultimately, the evidence suggests that polyamine metabolism in P. falciparum is a validated drug target worth exploiting.
Topics: Animals; Humans; Malaria, Falciparum; Plasmodium falciparum; Polyamines; Protozoan Proteins
PubMed: 19997948
DOI: 10.1007/s00726-009-0424-7 -
Nature Nov 1976
Topics: Blood; Cell Differentiation; Child; Child, Preschool; Humans; Infant; Plasmodium falciparum
PubMed: 794731
DOI: 10.1038/264271a0 -
Current Opinion in Structural Biology Dec 2013Malaria remains the world's most prevalent human parasitic disease. Because of the rapid spread of drug resistance in parasites, there is an urgent need to identify... (Review)
Review
Malaria remains the world's most prevalent human parasitic disease. Because of the rapid spread of drug resistance in parasites, there is an urgent need to identify diverse new drug targets. One group of proteases that are emerging as targets for novel antimalarials are the metalloaminopeptidases. These enzymes catalyze the removal of the N-terminal amino acids from proteins and peptides. Given the restricted specificities of each of these enzymes for different N-terminal amino acids, it is thought that they act in concert to facilitate protein turnover. Here we review recent structure and functional data relating to the development of the Plasmodium falciparum metalloaminopeptidases as drug targets.
Topics: Animals; Humans; Molecular Targeted Therapy; Peptide Hydrolases; Plasmodium falciparum
PubMed: 23948130
DOI: 10.1016/j.sbi.2013.07.015 -
FEBS Letters Jun 2000Plasmodium falciparum causes the most lethal form of malaria in humans and is responsible for over two million deaths per year. The development of a vaccine against this... (Review)
Review
Plasmodium falciparum causes the most lethal form of malaria in humans and is responsible for over two million deaths per year. The development of a vaccine against this parasite is an urgent priority and potential protein targets include those on the surface of the asexual merozoite stage, the form that invades the host erythrocyte. The development of methods to transfect P. falciparum has enabled the construction of gain-of-function and loss-of-function mutants and provided new strategies to analyse the role of parasite proteins. In this review, we describe the use of this technology to examine the role of merozoite antigens in erythrocyte invasion and to address their potential as vaccine candidates.
Topics: Animals; Antigens, Protozoan; Erythrocytes; Humans; Plasmodium falciparum; Protozoan Vaccines
PubMed: 10878256
DOI: 10.1016/s0014-5793(00)01703-8 -
Genes May 2021Genomics has revolutionised the study of the biology of parasitic diseases. The first Eukaryotic parasite to have its genome sequenced was the malaria parasite . Since... (Review)
Review
Genomics has revolutionised the study of the biology of parasitic diseases. The first Eukaryotic parasite to have its genome sequenced was the malaria parasite . Since then, genomics has continued to lead the way in the study of the genome biology of parasites, both in breadth-the number of species' genomes sequenced-and in depth-massive-scale genome re-sequencing of several key species. Here, we review some of the insights into the biology, evolution and population genetics of gained from genome sequencing, and look at potential new avenues in the future genome-scale study of its biology.
Topics: Epigenome; Genome, Protozoan; Humans; Malaria; Plasmodium falciparum; Polymorphism, Genetic
PubMed: 34070769
DOI: 10.3390/genes12060843 -
Scientific Reports Feb 2020The epigenome of the malaria parasite, Plasmodium falciparum, is associated with regulation of various essential processes in the parasite including control of...
The epigenome of the malaria parasite, Plasmodium falciparum, is associated with regulation of various essential processes in the parasite including control of proliferation during asexual development as well as control of sexual differentiation. The unusual nature of the epigenome has prompted investigations into the potential to target epigenetic modulators with novel chemotypes. Here, we explored the diversity within a library of 95 compounds, active against various epigenetic modifiers in cancerous cells, for activity against multiple stages of P. falciparum development. We show that P. falciparum is differentially susceptible to epigenetic perturbation during both asexual and sexual development, with early stage gametocytes particularly sensitive to epi-drugs targeting both histone and non-histone epigenetic modifiers. Moreover, 5 compounds targeting histone acetylation and methylation show potent multistage activity against asexual parasites, early and late stage gametocytes, with transmission-blocking potential. Overall, these results warrant further examination of the potential antimalarial properties of these hit compounds.
Topics: Acetylation; Enzyme Inhibitors; Epigenesis, Genetic; Histone Code; Life Cycle Stages; Methylation; Plasmodium falciparum; Small Molecule Libraries
PubMed: 32047203
DOI: 10.1038/s41598-020-59298-4