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Eukaryotic Cell Apr 2011Malaria is caused by intraerythrocytic protozoan parasites belonging to Plasmodium spp. (phylum Apicomplexa) that produce significant morbidity and mortality, mostly in... (Review)
Review
Malaria is caused by intraerythrocytic protozoan parasites belonging to Plasmodium spp. (phylum Apicomplexa) that produce significant morbidity and mortality, mostly in developing countries. Plasmodium parasites have a complex life cycle that includes multiple stages in anopheline mosquito vectors and vertebrate hosts. During the life cycle, the parasites undergo several cycles of extreme population growth within a brief span, and this is critical for their continued transmission and a contributing factor for their pathogenesis in the host. As with other eukaryotes, successful mitosis is an essential requirement for Plasmodium reproduction; however, some aspects of Plasmodium mitosis are quite distinct and not fully understood. In this review, we will discuss the current understanding of the architecture and key events of mitosis in Plasmodium falciparum and related parasites and compare them with the traditional mitotic events described for other eukaryotes.
Topics: Animals; Humans; Malaria, Falciparum; Mitosis; Plasmodium falciparum; Spindle Apparatus
PubMed: 21317311
DOI: 10.1128/EC.00314-10 -
Biomolecules Jul 2019The survival of the human malaria parasite under the physiologically distinct environments associated with their development in the cold-blooded invertebrate mosquito... (Review)
Review
The survival of the human malaria parasite under the physiologically distinct environments associated with their development in the cold-blooded invertebrate mosquito vectors and the warm-blooded vertebrate human host requires a genome that caters to adaptability. To this end, a robust stress response system coupled to an efficient protein quality control system are essential features of the parasite. Heat shock proteins constitute the main molecular chaperone system of the cell, accounting for approximately two percent of the malaria genome. Some heat shock proteins of parasites constitute a large part (5%) of the 'exportome' (parasite proteins that are exported to the infected host erythrocyte) that modify the host cell, promoting its cyto-adherence. In light of their importance in protein folding and refolding, and thus the survival of the parasite, heat shock proteins of have been a major subject of study. Emerging evidence points to their role not only being cyto-protection of the parasite, as they are also implicated in regulating parasite virulence. In undertaking their roles, heat shock proteins operate in networks that involve not only partners of parasite origin, but also potentially functionally associate with human proteins to facilitate parasite survival and pathogenicity. This review seeks to highlight these interplays and their roles in parasite pathogenicity. We further discuss the prospects of targeting the parasite heat shock protein network towards the developments of alternative antimalarial chemotherapies.
Topics: Animals; Heat-Shock Proteins; Humans; Plasmodium falciparum; Virulence
PubMed: 31340488
DOI: 10.3390/biom9070295 -
Combinatorial Chemistry & High... Feb 2005X-ray crystallography is a technique which is finding increasing utility in the effort to find new antimalarial drugs. This is in spite of the serious difficulties often... (Review)
Review
X-ray crystallography is a technique which is finding increasing utility in the effort to find new antimalarial drugs. This is in spite of the serious difficulties often encountered in obtaining sufficient quantities of protein to crystallize. This review provides an overview of the Plasmodium falciparum proteins which have been crystallized with bound inhibitors and the methodology employed in the heterologous expression of these proteins. Lactate dehydrogenase, plasmepsin II, and triosphosphate isomerase are the most advanced targets of structure-based drug design, but nine other P. falciparum proteins have been crystallized with inhibitors as well, and this is clearly an area which is moving very quickly. Some consideration will also be given to the limitations of structure-based drug discovery with respect to known antimalarial drugs.
Topics: Animals; Antimalarials; Crystallography, X-Ray; Plasmodium falciparum; Protozoan Proteins
PubMed: 15720193
DOI: 10.2174/1386207053328093 -
Molecular and Biochemical Parasitology Jul 2014The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family has a key role in parasite survival, transmission, and virulence. PfEMP1 are exported to the... (Review)
Review
The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family has a key role in parasite survival, transmission, and virulence. PfEMP1 are exported to the erythrocyte membrane and mediate binding of infected erythrocytes to the endothelial lining of blood vessels. This process aids parasite survival by avoiding spleen-dependent killing mechanisms, but it is associated with adhesion-based disease complications. Switching between PfEMP1 proteins enables parasites to evade host immunity and modifies parasite tropism for different microvascular beds. The PfEMP1 protein family is one of the most diverse adhesion modules in nature. This review covers PfEMP1 adhesion domain classification and the significant role it is playing in deciphering and deconvoluting P. falciparum cytoadhesion and disease.
Topics: Animals; Humans; Malaria, Falciparum; Plasmodium falciparum; Protein Binding; Protein Structure, Tertiary; Protozoan Proteins; Receptors, Cell Surface
PubMed: 25064606
DOI: 10.1016/j.molbiopara.2014.07.006 -
Molecular Microbiology Jul 2015The pathogenicity of Plasmodium falciparum is partly due to parasite-induced host cell modifications. These modifications are facilitated by exported P. falciparum...
The pathogenicity of Plasmodium falciparum is partly due to parasite-induced host cell modifications. These modifications are facilitated by exported P. falciparum proteins, collectively referred to as the exportome. Export of several hundred proteins is mediated by the PEXEL/HT, a protease cleavage site. The PEXEL/HT is usually comprised of five amino acids, of which R at position 1, L at position 3 and E, D or Q at position 5 are conserved and important for export. Non-canonical PEXEL/HTs with K or H at position 1 and/or I at position 3 are presently considered non-functional. Here, we show that non-canonical PEXEL/HT proteins are overrepresented in P. falciparum and other Plasmodium species. Furthermore, we show that non-canonical PEXEL/HTs can be cleaved and can promote export in both a REX3 and a GBP reporter, but not in a KAHRP reporter, indicating that non-canonical PEXEL/HTs are functional in concert with a supportive sequence environment. We then selected P. falciparum proteins with a non-canonical PEXEL/HT and show that some of these proteins are exported and that their export depends on non-canonical PEXEL/HTs. We conclude that PEXEL/HT plasticity is higher than appreciated and that non-canonical PEXEL/HT proteins cannot categorically be excluded from Plasmodium exportome predictions.
Topics: Amino Acid Motifs; Host-Parasite Interactions; Peptide Hydrolases; Plasmodium falciparum; Protein Processing, Post-Translational; Protein Transport; Protozoan Proteins
PubMed: 25850860
DOI: 10.1111/mmi.13024 -
Current Drug Targets 2018The Plasmodium falciparum cysteine proteases, also known as falcipains, are involved in different erythrocytic cycle processes of the malaria parasite, e.g. hydrolysis... (Review)
Review
BACKGROUND
The Plasmodium falciparum cysteine proteases, also known as falcipains, are involved in different erythrocytic cycle processes of the malaria parasite, e.g. hydrolysis of host haemoglobin, erythrocyte invasion, and erythrocyte rupture. With the biochemical characterization of four falcipains so far, FP-2 (falcipain-2) and FP-3 (falcipain-3), members of the papain-like CAC1 family, are essential haemoglobinases. They could therefore be referred to as potential anti-malarial drug targets in the search for novel therapies, which could ease the burden caused by the increasing resistance to current antimalarial drugs.
OBJECTIVES
This review provides a summary of the most important results, highlighting the drug design approaches essential for the understanding of the mechanism of inhibition and discovery of inhibitors against cysteine proteases from P. falciparum.
RESULTS
Rational and computer-aided drug discovery approaches for the design of promising falcipain inhibitors are described herein, with a focus on a variety of structure-based and ligand-based modeling approaches. Moreover, the key features of ligand recognition against these targets are emphasized.
CONCLUSION
This review would be of interest to scientists engaged in the development of drug design strategies to target the cysteine proteases, FP-2 and FP-3.
Topics: Antimalarials; Computer-Aided Design; Cysteine Proteinase Inhibitors; Drug Design; Drug Development; Plasmodium falciparum; Structure-Activity Relationship
PubMed: 28003005
DOI: 10.2174/1389450117666161221122432 -
The Journal of Antimicrobial... Mar 2010The in vitro selection of antimicrobial resistance in important pathogens can provide critical information on the genetic basis of drug resistance, and such information... (Review)
Review
The in vitro selection of antimicrobial resistance in important pathogens can provide critical information on the genetic basis of drug resistance, and such information can be used to predict, anticipate and even contain the spread of resistance in clinical practice. For instance, the discovery of the role of pfmdr1 in mefloquine resistance in malaria parasites resulted from in vitro studies. However, the in vitro selection of resistance is difficult, challenging and time consuming. In this review, we discuss the key parameters that impact on the efficiency of the in vitro selection of resistance, and propose strategies to improve and streamline this process.
Topics: Animals; Antimalarials; Drug Resistance; Parasitology; Plasmodium falciparum; Selection, Genetic
PubMed: 20022938
DOI: 10.1093/jac/dkp449 -
Biochemical Society Transactions Aug 1999
Review
Topics: Animals; Cell Adhesion; Endothelium, Vascular; Erythrocytes; Glycosylation; Humans; Liver; Malaria, Falciparum; Plasmodium falciparum; Polysaccharides
PubMed: 10917627
DOI: 10.1042/bst0270487 -
Parasitology 1992Molecular characterization of the Plasmodium falciparum genome has led to identification of polymorphic loci and the mechanisms generating genetic diversity in this... (Review)
Review
Molecular characterization of the Plasmodium falciparum genome has led to identification of polymorphic loci and the mechanisms generating genetic diversity in this parasite. This information has resulted in the development of molecular methods to type parasite diversity in the field. Consequently, we are now in a position to describe the population genetics and dynamics of P. falciparum. The limited number of field studies that have been conducted to date have revealed an extraordinary degree of genetic diversity in natural parasite populations. Heterozygous recombination which occurs during meiosis appears to be one mechanism for generating genetic diversity. The rate at which such recombination occurs in natural parasite populations defines the genetic structure of the parasite population and can influence the ability of the parasite to respond to selection pressure. The high frequency of single genotype infections and the female-biased gametocyte sex ratios found in hyperendemic malaria areas suggest that self-fertilization occurs frequently. Population-wide surveys of allele frequencies in endemic areas have, however, shown no evidence of linkage disequilibrium and are consistent with a panmictic population structure. We argue that these studies have only sampled symptomatic infections, within which rare or recombinant genotypes may be disproportionately represented. They also take no account of the spatial structure of P. falciparum populations. Systematic investigations of the amount of heterozygosity in small areas as part of population-wide surveys are required to define the genetic structure of P. falciparum populations. Population dynamic studies which consider genetic heterogeneity of P. falciparum have shown fluctuations of different serotypes in space and time. The host immune response appears to play an important role in generating these dynamics. Integrated field and laboratory studies, which consider the interaction between population genetics and dynamics, will be necessary to describe the population biology of P. falciparum.
Topics: Animals; Antigenic Variation; Genetic Variation; Humans; Malaria, Falciparum; Plasmodium falciparum; Population Dynamics
PubMed: 1589299
DOI: 10.1017/s0031182000075235 -
Expert Reviews in Molecular Medicine May 2009Severe malaria has a high mortality rate (15-20%) despite treatment with effective antimalarial drugs. Adjunctive therapies for severe malaria that target the underlying... (Review)
Review
Severe malaria has a high mortality rate (15-20%) despite treatment with effective antimalarial drugs. Adjunctive therapies for severe malaria that target the underlying disease process are therefore urgently required. Adhesion of erythrocytes infected with Plasmodium falciparum to human cells has a key role in the pathogenesis of life-threatening malaria and could be targeted with antiadhesion therapy. Parasite adhesion interactions include binding to endothelial cells (cytoadherence), rosetting with uninfected erythrocytes and platelet-mediated clumping of infected erythrocytes. Recent research has started to define the molecular mechanisms of parasite adhesion, and antiadhesion therapies are being explored. However, many fundamental questions regarding the role of parasite adhesion in severe malaria remain unanswered. There is strong evidence that rosetting contributes to severe malaria in sub-Saharan Africa; however, the identity of other parasite adhesion phenotypes that are implicated in disease pathogenesis remains unclear. In addition, the possibility of geographic variation in adhesion phenotypes causing severe malaria, linked to differences in malaria transmission levels and host immunity, has been neglected. Further research is needed to realise the untapped potential of antiadhesion adjunctive therapies, which could revolutionize the treatment of severe malaria and reduce the high mortality rate of the disease.
Topics: Animals; Bacterial Adhesion; Cells, Cultured; Endothelial Cells; Erythrocytes; Humans; Immunity; Malaria; Plasmodium falciparum
PubMed: 19467172
DOI: 10.1017/S1462399409001082