-
Mini Reviews in Medicinal Chemistry Jul 2013Plasmodium falciparum has a specific metabolism of particular interest because several of its features, with respect to the host human ones, are potential... (Review)
Review
Plasmodium falciparum has a specific metabolism of particular interest because several of its features, with respect to the host human ones, are potential pharmacological targets. Such features have been more intensely investigated since 2002, thanks to the full sequencing of the genome of P. falciparum. In this review, we are interested in the potential metabolic targets of therapeutic interest identified and investigated over the past decade in terms of lead-to-drug development.
Topics: Animals; Antimalarials; Plasmodium falciparum
PubMed: 23746057
DOI: 10.2174/13895575113139990060 -
Drug Resistance Updates : Reviews and... 2002Numerous approaches have been employed to identify the molecules responsible for drug resistance in the human malaria parasite Plasmodium falciparum. However, it was not... (Review)
Review
Numerous approaches have been employed to identify the molecules responsible for drug resistance in the human malaria parasite Plasmodium falciparum. However, it was not until the recent development of stable transfection in this parasite that it became possible to prove the role of particular genes in drug resistance and, perhaps more importantly, to characterise the nature of the specific mutations that contribute the resistance phenotype. In this review, the contribution of various molecular genetic approaches to the dissection of drug resistance in P. falciparum is described. Future possibilities in this field are also outlined in the light of recent technological advances.
Topics: Animals; Drug Resistance; Molecular Biology; Phenotype; Plasmodium falciparum; Transfection
PubMed: 12237080
DOI: 10.1016/s1368-7646(02)00085-7 -
Malaria Journal Nov 2017Post-translational modifications (PTMs) constitute a huge group of chemical modifications increasing the complexity of the proteomes of living beings. PTMs have been...
BACKGROUND
Post-translational modifications (PTMs) constitute a huge group of chemical modifications increasing the complexity of the proteomes of living beings. PTMs have been discussed as potential anti-malarial drug targets due to their involvement in many cell processes. O-GlcNAcylation is a widespread PTM found in different organisms including Plasmodium falciparum. The aim of this study was to identify O-GlcNAcylated proteins of P. falciparum, to learn more about the modification process and to understand its eventual functions in the Apicomplexans.
METHODS
The P. falciparum strain 3D7 was amplified in erythrocytes and purified. The proteome was checked for O-GlcNAcylation using different methods. The level of UDP-GlcNAc, the donor of the sugar moiety for O-GlcNAcylation processes, was measured using high-pH anion exchange chromatography. O-GlcNAcylated proteins were enriched and purified utilizing either click chemistry labelling or adsorption on succinyl-wheat germ agglutinin beads. Proteins were then identified by mass-spectrometry (nano-LC MS/MS).
RESULTS
While low when compared to MRC5 control cells, P. falciparum disposes of its own pool of UDP-GlcNAc. By using proteomics methods, 13 O-GlcNAcylated proteins were unambiguously identified (11 by click-chemistry and 6 by sWGA-beads enrichment; 4 being identified by the 2 approaches) in late trophozoites. These proteins are all part of pathways, functions and structures important for the parasite survival. By probing clicked-proteins with specific antibodies, Hsp70 and α-tubulin were identified as P. falciparum O-GlcNAc-bearing proteins.
CONCLUSIONS
This study is the first report on the identity of P. falciparum O-GlcNAcylated proteins. While the parasite O-GlcNAcome seems close to those of other species, the structural differences exhibited by the proteomes provides a glimpse of innovative therapeutic paths to fight malaria. Blocking biosynthesis of UDP-GlcNAc in the parasites is another promising option to reduce Plasmodium life cycle.
Topics: Acetylglucosamine; Glycosylation; Plasmodium falciparum; Protein Processing, Post-Translational; Proteome; Protozoan Proteins
PubMed: 29187233
DOI: 10.1186/s12936-017-2131-2 -
Mini Reviews in Medicinal Chemistry Feb 2006Over 300 million cases of malaria each year cause significant morbidity and mortality. Growing drug-resistance among the Plasmodia that cause malaria motivates the... (Review)
Review
Over 300 million cases of malaria each year cause significant morbidity and mortality. Growing drug-resistance among the Plasmodia that cause malaria motivates the development of additional anti-malarial drugs. This review summarizes the current state of knowledge about potential drug targets for malaria. The recently sequenced malaria genome data clarifies parasite metabolic pathways, and more metabolic targets have been identified.
Topics: Animals; Antimalarials; DNA Replication; Drug Resistance; Genome, Protozoan; Lipid Metabolism; Plasmodium falciparum; Transcription, Genetic
PubMed: 16472186
DOI: 10.2174/138955706775475957 -
Molecular and Biochemical Parasitology Sep 1998Transfection has facilitated a functional analysis of transcriptional processes in the human malarial parasite Plasmodium falciparum, providing the first fascinating... (Review)
Review
Transfection has facilitated a functional analysis of transcriptional processes in the human malarial parasite Plasmodium falciparum, providing the first fascinating glimpses into the mechanisms regulating parasite development and pathogenicity. Here we review our rapidly evolving knowledge of what constitutes a promoter, what factors regulate promoter activity and how this activity affects the manifestation of the disease.
Topics: Animals; Chromatin; Gene Expression Regulation; Gene Expression Regulation, Developmental; Genes, Protozoan; Humans; Plasmodium falciparum; Promoter Regions, Genetic; Protozoan Proteins
PubMed: 9803410
DOI: 10.1016/s0166-6851(98)00110-8 -
SAR and QSAR in Environmental Research Apr 2020Support vector machine (SVM) and general regression neural network (GRNN) were used to develop classification models for predicting the antimalarial activity against ....
Support vector machine (SVM) and general regression neural network (GRNN) were used to develop classification models for predicting the antimalarial activity against . Only 15 molecular descriptors were used to build the classification models for the antimalarial activities of 4750 compounds, which were divided into a training set (3887 compounds) and a test set (863 compounds). For the SVM model, its prediction accuracies are 89.5% for the training set and 87.3% for the test set. For the GRNN model, the prediction accuracies for the two sets are 99.7% and 88.9%, respectively. Both SVC and GRNN models have better prediction ability than the classification model based on binary logistic regression (BLR) analysis. Compared with previously published classification models both SVC and GRNN models are satisfactory in predicting antimalarial activities of compounds with in addition of fewer descriptors.
Topics: Antimalarials; Neural Networks, Computer; Plasmodium falciparum; Quantitative Structure-Activity Relationship; Support Vector Machine
PubMed: 32191533
DOI: 10.1080/1062936X.2020.1740890 -
ACS Infectious Diseases Nov 2016MMV007564 is a novel antimalarial benzimidazolyl piperidine chemotype identified in cellular screens. To identify the genetic determinant of MMV007564 resistance,...
MMV007564 is a novel antimalarial benzimidazolyl piperidine chemotype identified in cellular screens. To identify the genetic determinant of MMV007564 resistance, parasites were cultured in the presence of the compound to generate resistant lines. Whole genome sequencing revealed distinct mutations in the gene named Plasmodium falciparum cyclic amine resistance locus (pfcarl), encoding a conserved protein of unknown function. Mutations in pfcarl are strongly associated with resistance to a structurally unrelated class of compounds, the imidazolopiperazines, including KAF156, currently in clinical trials. Our data demonstrate that pfcarl mutations confer resistance to two distinct compound classes, benzimidazolyl piperidines and imidazolopiperazines. However, MMV007564 and the imidazolopiperazines, KAF156 and GNF179, have different timings of action in the asexual blood stage and different potencies against the liver and sexual blood stages. These data suggest that pfcarl is a multidrug-resistance gene rather than a common target for benzimidazolyl piperidines and imidazolopiperazines.
Topics: Antimalarials; Drug Resistance; Humans; Life Cycle Stages; Malaria, Falciparum; Mutation; Piperidines; Plasmodium falciparum; Protozoan Proteins
PubMed: 27933786
DOI: 10.1021/acsinfecdis.6b00025 -
The Journal of Eukaryotic Microbiology 2014Malaria plagues one out of every 30 humans and contributes to almost a million deaths, and the problem could worsen. Our current therapeutic options are compromised by... (Review)
Review
Malaria plagues one out of every 30 humans and contributes to almost a million deaths, and the problem could worsen. Our current therapeutic options are compromised by emerging resistance by the parasite to our front line drugs. It is thus imperative to better understand the basic biology of the parasite and develop novel drugs to stem this disease. The most facile approach to analyse a gene's function is to remove it from the genome or inhibit its activity. Although genetic manipulation of the human malaria parasite Plasmodium falciparum is a relatively standard procedure, there is no optimal method to perturb genes essential to the intraerythrocytic development cycle--the part of the life cycle that produces the clinical manifestation of malaria. This is a severe impediment to progress because the phenotype we wish to study is exactly the one that is so elusive. In the absence of any utilitarian way to conditionally delete essential genes, we are prevented from investigating the parasite's most vulnerable points. This review aims to focus on the development of tools identifying essential genes of P. falciparum and our ability to elicit phenotypic mutation.
Topics: Animals; Erythrocytes; Genes, Protozoan; Genome, Protozoan; Life Cycle Stages; Mutation; Phenotype; Plasmodium falciparum
PubMed: 25227912
DOI: 10.1111/jeu.12176 -
Biology of the Cell 1988Gametocyte development has been studied in synchronous cultures of P. falciparum. These studies have confirmed that maturation of this stage occurs over 7 days and... (Review)
Review
Gametocyte development has been studied in synchronous cultures of P. falciparum. These studies have confirmed that maturation of this stage occurs over 7 days and doubling of the DNA content takes place early in the development stage. There appears to be no direct relationship between the number of gametocytes ingested by a mosquito and the oocyst load, nor between the latter and the number of salivary gland sporozoites. The variability in oocyst load could in part be explained by the individual differences in digestion speed of mosquitoes. The number of salivary gland sporozoites and thus also that of sporozoites inoculated per bite of a mosquito is influenced by the number of blood meals which the mosquito has ingested after the infectious blood meal. Moreover, the longer the mosquito survives the more infective it becomes due to increased density of sporozoites in the glands. Anti-sporozoite antibodies present in the blood meal of an already infected mosquito do not hinder migration of sporozoites to the salivary glands. It has been demonstrated that monoclonal antibodies directed against epitopes of gamete surface proteins of molecular weight of 230, 45/48 and 25 kDa could block sporogony. Transmission blocking antibodies are also present in the sera of individuals exposed to natural transmission. These epitopes of the target proteins are non-repetitive and conformational and thus rendered non-reactive by reduction. Moreover, some of these surface proteins are glycosylated and/or acylated, and may depend on the presence of the native disulphide bonds for the preservation of immune reactivity. These post-translational modifications have made screening of gene libraries with immunoproteins difficult.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Gametogenesis; Plasmodium falciparum; Spores
PubMed: 3067802
DOI: 10.1016/0248-4900(88)90083-4 -
Malaria Journal Apr 2020A previous study reported that the malaria parasite Plasmodium falciparum enters an altered growth state upon extracellular withdrawal of the essential amino acid...
BACKGROUND
A previous study reported that the malaria parasite Plasmodium falciparum enters an altered growth state upon extracellular withdrawal of the essential amino acid isoleucine. Parasites slowed transit through the cell cycle when deprived of isoleucine prior to the onset of S-phase.
METHODS
This project was undertaken to study at higher resolution, how isoleucine withdrawal affects parasite growth. Parasites were followed at regular intervals across an extended isoleucine deprivation time course across the cell cycle using flow cytometry.
RESULTS
These experiments revealed that isoleucine-deprived parasites never exit the cell cycle, but instead continuously grow at a markedly reduced pace. Moreover, slow growth occurs only if isoleucine is removed prior to the onset of schizogony. After S-phase commenced, the parasite is insensitive to isoleucine depletion and transits through the cell cycle at the normal pace.
CONCLUSIONS
The markedly different response of the parasite to isoleucine withdrawal before or after the onset of DNA replication is reminiscent of the nutrient-dependent G1 cell cycle checkpoints described in other organisms.
Topics: Cell Cycle; DNA Replication; DNA, Protozoan; Erythrocytes; Isoleucine; Plasmodium falciparum
PubMed: 32268910
DOI: 10.1186/s12936-020-03220-w