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Tropical Biomedicine Sep 2020Malaria is one of the most dangerous infectious diseases due to its high infection and mortality rates, especially in the tropical belt. Plasmodium falciparum (P.... (Review)
Review
Malaria is one of the most dangerous infectious diseases due to its high infection and mortality rates, especially in the tropical belt. Plasmodium falciparum (P. falciparum), the most virulent malaria parasite in humans, was recently reported to develop resistance against the final efficient antimalarial drug, artemisinin. Little is known about the resistance mechanisms, which further complicates the problem as a proper counteraction is unable to be taken. Hence, the understanding of drug mode of action and its molecular target is valuable knowledge that needs to be considered to develop the next generation of antimalarial drugs. P. falciparum protein kinase (Pf PK) is an attractive target for antimalarial chemotherapy due to its vital roles in all P. falciparum life stages. Moreover, overall structural differences and the presence of unique Pf PKs that are absent in human kinome, suggesting specific inhibition of Pf PK without affecting human cells is achievable. To date, at least 86 eukaryotic protein kinases have been identified in P. falciparum kinome, by which less than 40 were validated as potential targets at the erythrocytes stage. In this review, recent progress of the furthest validated Pf PKs; Pf Nek-1, Pf CDPK1, Pf CDPK4, Pf PKG, and Pf CLK-3 will be briefly discussed.
Topics: Antimalarials; Humans; Malaria, Falciparum; Plasmodium falciparum; Protein Kinase Inhibitors; Protein Kinases
PubMed: 33612795
DOI: 10.47665/tb.37.3.822 -
Frontiers in Immunology 2019Malaria infections remain a serious global health problem in the world, particularly among children and pregnant women in Sub-Saharan Africa. Moreover, malaria control... (Review)
Review
Malaria infections remain a serious global health problem in the world, particularly among children and pregnant women in Sub-Saharan Africa. Moreover, malaria control and elimination is hampered by rapid development of resistance by the parasite and the vector to commonly used antimalarial drugs and insecticides, respectively. Therefore, vaccine-based strategies are sorely needed, including those designed to interrupt disease transmission. However, a prerequisite for such a vaccine strategy is the understanding of both the human and vector immune responses to parasite developmental stages involved in parasite transmission in both man and mosquito. Here, we review the naturally acquired humoral and cellular responses to sexual stages of the parasite while in the human host and the vector. In addition, updates on current anti-gametocyte, anti-gamete, and anti-mosquito transmission blocking vaccines are given. We conclude with our views on some important future directions of research into sexual stage immunity relevant to the search for the most appropriate transmission-blocking vaccine.
Topics: Animals; Antigens, Protozoan; Host-Parasite Interactions; Humans; Life Cycle Stages; Malaria Vaccines; Mosquito Vectors; Plasmodium falciparum
PubMed: 30804940
DOI: 10.3389/fimmu.2019.00136 -
The Korean Journal of Parasitology Dec 2015After invasion of red blood cells, malaria matures within the cell by degrading hemoglobin avidly. For enormous protein breakdown in trophozoite stage, many efficient...
After invasion of red blood cells, malaria matures within the cell by degrading hemoglobin avidly. For enormous protein breakdown in trophozoite stage, many efficient and ordered proteolysis networks have been postulated and exploited. In this study, a potential interaction of a 60-kDa Plasmodium falciparum (Pf)-heat shock protein (Hsp60) and Pf-calpain, a cysteine protease, was explored. Pf-infected RBC was isolated and the endogenous Pf-Hsp60 and Pf-calpain were determined by western blot analysis and similar antigenicity of GroEL and Pf-Hsp60 was determined with anti-Pf-Hsp60. Potential interaction of Pf-calpain and Pf-Hsp60 was determined by immunoprecipitation and immunofluorescence assay. Mizoribine, a well-known inhibitor of Hsp60, attenuated both Pf-calpain enzyme activity as well as P. falciparum growth. The presented data suggest that the Pf-Hsp60 may function on Pf-calpain in a part of networks during malaria growth.
Topics: Amino Acid Sequence; Calpain; Chaperonin 60; Erythrocytes; Humans; Malaria, Falciparum; Molecular Sequence Data; Plasmodium falciparum; Protein Binding; Protozoan Proteins; Sequence Alignment
PubMed: 26797432
DOI: 10.3347/kjp.2015.53.6.665 -
Current Protein & Peptide Science 2016Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological... (Review)
Review
Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological agent P. falciparum is transmitted through the bite of the female Anopheles mosquito. The issue has escalated due to the emergence of resistant strains to most of the antimalarials used for the treatment including Chloroquine, Sulfadoxine-Pyrimethamine, and recently Artemisinin derivatives, which has led to diminished effectiveness and by consequence increased the severity of epidemic outbreaks. Due to the lack of effective compounds to treat these drug-resistant strains, the discovery or development of novel anti-malaria drugs is important. In this context, one strategy has been to find inhibitors of enzymes, which play an important role for parasite survival. Today, promising results have been obtained in this regard, involving the entire P. falciparum metabolism. These inhibitors could serve as leads in the search of a new chemotherapy against malaria. This review focuses on the achievements in recent years with regard to inhibition of enzymes used as targets for drug design against malaria.
Topics: Animals; Antimalarials; Drug Design; Humans; Metabolic Networks and Pathways; Plasmodium falciparum
PubMed: 26983887
DOI: 10.2174/1389203717999160226180353 -
Life Sciences Aug 2016Malaria is a life-threatening tropical disease, caused by the intracellular parasite Plasmodium falciparum. The World Health Organization counts malaria as one of the... (Review)
Review
Malaria is a life-threatening tropical disease, caused by the intracellular parasite Plasmodium falciparum. The World Health Organization counts malaria as one of the top ten causes of worldwide death. The unavailability of a successful malaria vaccine and the ever-increasing instances of drug resistance in the malaria parasite demand the discovery of new targets within P. falciparum for the development of next generation antimalarials. Fortunately, all apicomplexan parasites, including P. falciparum harbor a relict, non-photosynthetic plastid known as the apicoplast. The apicoplast is a semi-autonomous organelle within P. falciparum containing a 35kb circular genome. Despite a genome of its own, majority of the apicoplast proteins are encoded by the parasite nucleus and imported into the apicoplast. The organelle has been shown to be essential to P. falciparum survival and the loss the apicoplast manifests as a 'delayed death' response in the parasite. The apicoplast has evolved out of cyanobacteria in a complex, two step endosymbiotic event. As a result the architecture and the gene expression machinery of the apicoplast is quite bacteria-like and is susceptible to a wide range of antibiotics such as fosmidomycin, tetracycline, azithromycin, clindamycin and triclosan. The biosynthetic pathways for isoprenoids, fatty acids and heme operate within the malaria apicoplast, making the organelle an excellent target for drug development. The review focuses on the evolution, biology and the essentiality of the apicoplast within the malaria parasite and discusses some of the recent achievements towards the design and discovery of apicoplast targeted antimalarial compounds.
Topics: Animals; Antimalarials; Organelles; Plasmodium falciparum
PubMed: 27381078
DOI: 10.1016/j.lfs.2016.06.030 -
Trends in Parasitology Oct 2015Plasmodium falciparum blood stages export a large number of proteins into their host red blood cell, leading to changes to the infected cell that are pivotal for... (Review)
Review
Plasmodium falciparum blood stages export a large number of proteins into their host red blood cell, leading to changes to the infected cell that are pivotal for parasite survival and contribute to parasite virulence. To reach the host cell, exported proteins follow a multistep pathway that now has been revealed to be similar for different classes of exported proteins. Here we summarise the current understanding about the critical segments in protein export of P. falciparum blood stages and discuss recent findings highlighting protein export as a potential target for chemotherapeutic interventions.
Topics: Drug Delivery Systems; Erythrocytes; Host-Parasite Interactions; Humans; Plasmodium falciparum; Protein Transport; Protozoan Proteins
PubMed: 26433254
DOI: 10.1016/j.pt.2015.06.010 -
Scientific Reports Mar 2020Mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) confer resistance to several antimalarial drugs such as chloroquine (CQ) or piperaquine...
Mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) confer resistance to several antimalarial drugs such as chloroquine (CQ) or piperaquine (PPQ), a partner molecule in current artemisinin-based combination therapies. As a member of the Drug/Metabolite Transporter (DMT) superfamily, the vacuolar transporter PfCRT may translocate substrate molecule(s) across the membrane of the digestive vacuole (DV), a lysosome-like organelle. However, the physiological substrate(s), the transport mechanism and the functional regions of PfCRT remain to be fully characterized. Here, we hypothesized that identification of evolutionary conserved sites in a tertiary structural context could help locate putative functional regions of PfCRT. Hence, site-specific substitution rates were estimated over Plasmodium evolution at each amino acid sites, and the PfCRT tertiary structure was predicted in both inward-facing (open-to-vacuole) and occluded states through homology modeling using DMT template structures sharing <15% sequence identity with PfCRT. We found that the vacuolar-half and membrane-spanning domain (and especially the transmembrane helix 9) of PfCRT were more conserved, supporting that its physiological substrate is expelled out of the parasite DV. In the PfCRT occluded state, some evolutionary conserved sites, including positions related to drug resistance mutations, participate in a putative binding pocket located at the core of the PfCRT membrane-spanning domain. Through structural comparison with experimentally-characterized DMT transporters, we identified several conserved PfCRT amino acid sites located in this pocket as robust candidates for mediating substrate transport. Finally, in silico mutagenesis revealed that drug resistance mutations caused drastic changes in the electrostatic potential of the transporter vacuolar entry and pocket, facilitating the escape of protonated CQ and PPQ from the parasite DV.
Topics: Amino Acids; Antimalarials; Chloroquine; Drug Resistance; Evolution, Molecular; Membrane Transport Proteins; Mutation; Parasitic Sensitivity Tests; Phylogeny; Plasmodium falciparum; Protozoan Proteins; Quinolines; Vacuoles
PubMed: 32179795
DOI: 10.1038/s41598-020-61181-1 -
Frontiers in Cellular and Infection... 2015Malaria is a worldwide health problem leading the death of millions of people. The disease is induced by different species of protozoa parasites from the genus... (Review)
Review
Malaria is a worldwide health problem leading the death of millions of people. The disease is induced by different species of protozoa parasites from the genus Plasmodium. In humans, Plasmodium falciparum is the most dangerous species responsible for severe disease. Despite all efforts to establish the pathogenesis of malaria, it is far from being fully understood. In addition, resistance to existing drugs has developed in several strains and the development of new effective compounds to fight these parasites is a major issue. Recent discoveries indicate the potential role of the renin-angiotensin system (RAS) in malaria infection. Angiotensin receptors have not been described in the parasite genome, however several reports in the literature suggest a direct effect of angiotensin-derived peptides on different aspects of the host-parasite interaction. The aim of this review is to highlight new findings on the involvement of the RAS in parasite development and in the regulation of the host immune response in an attempt to expand our knowledge of the pathogenesis of this disease.
Topics: Host-Parasite Interactions; Humans; Malaria, Falciparum; Plasmodium falciparum; Renin-Angiotensin System
PubMed: 26779452
DOI: 10.3389/fcimb.2015.00103 -
The FEBS Journal Aug 2017Understanding the dynamic behaviour of the Plasmodium falciparum metabolism during infection can help identify targets for drug development. In this Commentary, we...
Understanding the dynamic behaviour of the Plasmodium falciparum metabolism during infection can help identify targets for drug development. In this Commentary, we highlight recently published studies in The FEBS Journal that cover mathematical modelling of glycolysis in P. falciparum and the identification and in vivo validation of metabolic drug targets.
Topics: Antimalarials; Glycolysis; Humans; Malaria; Models, Theoretical; Plasmodium falciparum
PubMed: 28834340
DOI: 10.1111/febs.14161 -
Nature Reviews. Microbiology Dec 2016This month's Genome Watch describes how whole-genome sequencing used for surveillance purposes has enabled the identification of new drug resistance markers in the...
This month's Genome Watch describes how whole-genome sequencing used for surveillance purposes has enabled the identification of new drug resistance markers in the malaria parasite.
Topics: Animals; Antimalarials; Drug Resistance; Genome, Protozoan; Humans; Malaria, Falciparum; Plasmodium falciparum; Sequence Analysis, DNA
PubMed: 27932794
DOI: 10.1038/nrmicro.2016.181