Download or read book Biochemical and Structural Characterization of Novel Drug Targets Regulating Polyamine Biosynthesis in the Human Malaria Parasite Plasmodium Falciparum written by Marni Williams and published by . This book was released on 2011 with total page 368 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Drug Targets for Plasmodium Falciparum Historic to Future Perspectives written by Mohammed Tarique and published by Springer Nature. This book was released on with total page 205 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Structural and Functional Validation of S adenosylmethionine Decarboxylase as a Novel Drug Target in the Malaria Parasite Plasmodium Falciparum written by Dina Coertzen and published by . This book was released on 2014 with total page 236 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is considered the most prevailing human parasitic disease. Despite various chemotherapeutic interventions being available, the parasite responsible for the most lethal form of malaria, Plasmodium falciparum, is continuously developing resistance towards drugs targeted against it. This, therefore, necessitates the need for validation of new antimalarial development. Polyamine biosynthetic enzymes, particularly S-adenosylmethionine-L-decarboxylase (PfAdoMetDC), has been identified as a suitable drug target for protozoan parasitic diseases due to its essential role in cell proliferation. Furthermore, in Plasmodium polyamine biosynthesis, PfAdoMetDC is organised into a unique bifunctional complex with ornithine decarboxylase (PfAdoMetDC/ODC) covalently linked by a hinge region, distinguishing this enzyme as unique a drug target. However, inhibitors targeting this pathway have not been successful in clinical assessment, creating the need for further research in identifying novel inhibitors. This study focused on the structural and functional characterisation of protein-specific properties of the AdoMetDC domain in P. falciparum parasites, as well as identifying novel inhibitors targeting this enzyme as a potential antimalarial therapeutic intervention. In order to develop novel inhibitors specifically targeting PfAdoMetDC through a structure-based drug discovery approach, the three-dimensional structure is required. However, due to a lack of structural and functional characterisation, determination of the crystal structure has been challenging. Heterologous expression of monofunctional PfAdoMetDC was achieved from a wild-type construct of the PfAdoMetDC domain including the covalently linked hinge region. In chapter 2, deletion of a large non-homologous, low-complexity parasite-specific insert (A3) in monofunctional PfAdoMetDC resulted in an increased yield, purity and sample homogeneity, whilst maintaining protein functionality and structural integrity. However, truncation of the proposed non-essential hinge region resulted in low-level expression of insoluble protein aggregates and a complete loss of protein activity, indicating that the hinge region is essential for monofunctional PfAdoMetDC. However, in the absence of the three-dimensional PfAdoMetDC crystal structure, novel derivatives of a well-known AdoMetDC inhibitor, MDL73811, were tested for their activity against heterologous PfAdoMetDC, as well as their potency against P. falciparum parasites, in chapter 3. The compound Genz-644131 was identified as a lead inhibitor of PfAdoMetDC, however, the poor membrane permeability of the compound resulted in low in vitro activity. Drug permeability of Genz-644131 into P. falciparum infected erythrocytes and its potency was significantly improved by its encapsulation into a novel immunoliposome based drug delivery system. The results presented here provide essential information for development of a unique strategy in obtaining suffiecient levels of fully active recombinant PfAdoMetDC of sufficient purity for crystallisation studies and subsequent structure-based drug design efforts. The combination of Genz-644131 with the novel drug delivery system, which markedly improved its potency against PfAdoMetDC may proof to be a viable antimalarial chemotherapeutic strategy for future investigations.
Download or read book Functional Biochemical and Structural Analyses of Two Plasmodium Membrane Proteins written by Amy Marigot Clarke and published by . This book was released on 2013 with total page 558 pages. Available in PDF, EPUB and Kindle. Book excerpt: Protozoan parasites of the genus Plasmodium are the causative agent of malaria. The most severe form of human malaria is caused by P. falciparum, responsible for approximately three quarters of a million deaths each year. One major problem in the treatment of malaria is resistance to existing chemotherapies. Consequently, there is an urgent need to identify and validate novel drug targets. A possible recently identified drug target is the PfNitA protein of P. falciparum which contains orthologues in other Plasmodium species but is absent from humans. The gene is annotated as a putative formate-nitrite transporter and orthologues are found in a range of prokaryotes as well as the lower eukaryotes algae and fungi. To determine the biological function of the protein, pfnita was expressed in Escherichia coli strains lacking the endogenous formate and nitrite transporters. In order to analyse the essentiality of the gene a reverse genetics approach was taken and the data discussed. Results indicate that the PfNitA protein is located in the plasma membrane and digestive vacuole of intraerythrocytic parasites suggesting a role in the uptake or excretion of metabolites. A second complexity with regard to treatment is the lack of a vaccine. A problem in crating a vaccine is antigenic variation. The PIR family of proteins contain a so-called hypervariable domain that has led to the suggestion that the family may play a role in antigenic variation. The objective of the work carried out in this thesis was to investigate the topology and structure of the PcCir2 protein of Plasmodium chabaudi, using E. coli as the expression host. The topology of Cir2 has been examined by means of reporter fusions and overexpression/purification studies undertaken towards crystallisation. As the PcCir2 amino acid sequence does not show significant homology to other proteins, structural data may provide insights into potential functional or binding domains.
Download or read book Characterization and Analysis of Novel Antimalarial Drug Targets Plasmodium Falciparum Phosphatidylinositol Kinases written by Anna Rose Sternberg and published by . This book was released on 2020 with total page 372 pages. Available in PDF, EPUB and Kindle. Book excerpt: Artemisinin-based combination therapy (ACT) is the first-line treatment recommended for uncomplicated Plasmodium falciparum infections by the World Health Organization (WHO). ACTs are composed of an artemisinin (ART) drug and a longer lasting partner drug, typically with a mechanism of action (MOA) different from ARTs. With the exception of ARTs, there is widespread resistance to all antimalarial drug classes previously recommended for use against P. falciparum. However, the appearance of delayed clearance phenotype (DCP) infections due to reduced ACT efficacy in Southeast Asia [Noedl et al., 2008] threatens our ability to successfully treat multi-drug resistant P. falciparum malaria with ACTs. This also indicates the era of ARTs as leading antimalarial drugs may be reaching an end, so there is desperate need for the development of novel and potent antimalarials for use in next generation therapies.
Download or read book Pyrimidine Biosynthesis in Human Malaria Parasite Plasmodium Falciparum written by and published by . This book was released on 2002 with total page 136 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Functional and Structural Characterization of the Unique Bifunctional Enzyme Complex Involved in Regulation of Polyamine Metabolism in Plasmodium Falciparum written by Lyn-Marie Birkholtz and published by . This book was released on 2002 with total page 221 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Biochemical Characterisation of Putrescine and Spermidine Uptake as a Potential Therapeutic Target Against the Human Malaria Parasite Plasmodium Falciparum written by Jandeli Niemand and published by . This book was released on 2011 with total page 262 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Functional Characterization of Cytochrome B5 Reductase and Its Electron Acceptor Cytochrome B5 in Plasmodium Falciparum written by Lucio Malvisi and published by . This book was released on 2009 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: ABSTRACT: Malaria is a disease of major public health importance, killing approximately one million people and causing about 250 million cases of fever annually. It mostly affects children under the age of five and pregnant women in many developing countries, making it a prominent issue in international health and maternal and child health. The most aggressive form of malaria is caused by the parasite Plasmodium falciparum which is responsible for 80% of infections and 90% of deaths from malaria, and is most prevalent in sub-Saharan Africa. Public Health interventions include the implementation of prevention programs, health education, and chemotherapy. The latter has experienced multiple problems in the past years whereby resistance of the parasite to the available drugs has emerged, rendering the majority of them ineffective. Furthermore, the high cost of those drugs represents a major obstacle to their dispensation in areas of the world where the affected people are often the less fortunate. The enzyme Cytochrome b5 Reductase (cb5r) and its electron acceptor Cytochrome b5 (cb5) play a role in fatty acid elongation, cholesterol biosynthesis, and cytochrome P450-mediated detoxification of xenobiotics. Therefore, these proteins are suitable as potential novel drug targets for malaria. These two proteins have been thoroughly studied in mammals but have to be characterized in microorganisms such as fungi and parasites, including Plasmodium falciparum. It is important to note that plant cb5r has been identified as a novel herbicidal target. Considering the close phylogenetic relationship between plant cb5r and Plasmodium falciparum cb5r, we conclude that these plant inhibitors may also serve as promising candidates for a new class of antimalarial drugs against the parasite. In this project, we want to obtain the biochemical and enzymatic characterization of cb5r and cb5 in order to establish whether these two proteins represent potential novel drug targets in Plasmodium falciparum malaria. This initial work may lead to the development of novel drugs which will consequently affect the field of public health with respect to drug delivery, drug resistance, and drug chemotherapy.
Download or read book Encyclopedia of Malaria written by and published by Springer. This book was released on 2018-07-12 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Encyclopedia of Malaria represents a vast databank of information about the study of malaria. It provides an overview of the historical, rapid and significant developments that have occurred in malaria research, including the 2002 genome sequencing of Plasmodium falciparum and its mosquito vector, Anopheles gambiae. This work provides a concise source of up-to-date research findings in the form of definitions and essays and present comprehensive coverage of topics from history to findings to diagnosis and treatment, written by recognized malaria researchers with practical experience. It appeals to a diverse audience, including malaria researchers, teachers, investigators and public health professionals.
Download or read book Polyamines in Fungi written by Laura Valdés-Santiago and published by CRC Press. This book was released on 2015-11-18 with total page 206 pages. Available in PDF, EPUB and Kindle. Book excerpt: It was not until recent years that the study of polyamines, their mechanisms of synthesis, and the roles they play in metabolism have flourished, becoming a fertile field of intense research. Polyamines in Fungi: Their Distribution, Metabolism, and Role in Cell Differentiation and Morphogenesis provides a complete overview of its topic. It is the f
Download or read book Toxoplasma Gondii written by Louis M. Weiss and published by Academic Press. This book was released on 2013-08-10 with total page 1109 pages. Available in PDF, EPUB and Kindle. Book excerpt: This 2e of Toxoplasma gondii reflects the significant advances in the field in the last 5 years, including new information on the genomics, epigenomics and proteomics of T. gondii as well as a new understanding of the population biology and genetic diversity of this organism. T. gondii remains the best model system for studying the entire Apicomplexa group of protozoans, which includes Malaria, making this new edition essential for a broad group of researchers and scientists. Toxoplasmosis is caused by a one-celled protozoan parasite known as T. gondii. The infection produces a wide range of clinical syndromes in humans, land and sea mammals, and various bird species. Most humans contract toxoplasmosis by eating contaminated, raw or undercooked meat (particularly pork), vegetables, or milk products; by coming into contact with the T. gondii eggs from cat feces; or by drinking contaminated water. The parasite damages the ocular and central nervous systems, causing behavioral and personality alterations as well as fatal necrotizing encephalitis. It is especially dangerous for the fetus of an infected pregnant woman and for individuals with compromised immune systems, such as HIV-infected patients. Completely updated, the 2e presents recent advances driven by new information on the genetics and genomics of the pathogen Provides the latest information concerning the epidemiology, diagnosis, treatment and prevention of toxoplasmosis Offers a single-source reference for a wide range of scientists and physicians working with this pathogen, including parasitologists, cell and molecular biologists, veterinarians, neuroscientists, physicians, and food scientists
Download or read book Biomedical Index to PHS supported Research written by and published by . This book was released on 1988 with total page 1108 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book The Malaria Genome Projects written by Irwin W. Sherman and published by World Scientific. This book was released on 2012 with total page 389 pages. Available in PDF, EPUB and Kindle. Book excerpt: The year 2012 marks the tenth anniversary of the announcement of the genome sequence of the human malaria parasite Plasmodium falciparum and that of its mosquito vector Anopheles. The genome sequences were a result of the Plasmodium falciparum Genome Project. This book covers in detail the biology of malaria parasites and the mosquitoes that transmit the disease, how the Genome Project came into being, the people who created it, and the cadre of scientists who are attempting to see the promise of the Project realized. The promise was: a more complete understanding of the genes of the parasite (and its vector) would provide a rational basis for the development of antimalarial drugs and vaccines, allow a better understanding of the regulation of the complex life cycle in the red blood and liver cells of the human, identify the genes the parasite uses to thwart the host immune response and the ways in which the parasite evades cure by drug treatments, as well as leading to more effective measures of control transmission. The hope was that cracking the genetic code of Plasmodium and Anopheles would reveal the biochemical Achilles heel of the parasite and its vector, leading to the development of novel drugs and better methods of control, and by finding the targets of protective immunity could result in the manufacture of effective vaccines. Through a historic approach, this book will allow for those new to the field, or those with insufficient background in the sciences, to have an easier entry point. Even scientists already working in the field may better appreciate how discoveries made in the past can impact the direction of future research.
Download or read book Cumulated Index Medicus written by and published by . This book was released on 1995 with total page 1584 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Index Medicus written by and published by . This book was released on 2003 with total page 1902 pages. Available in PDF, EPUB and Kindle. Book excerpt: Vols. for 1963- include as pt. 2 of the Jan. issue: Medical subject headings.
Download or read book Malaria written by Irwin W. Sherman and published by Amer Society for Microbiology. This book was released on 1998-01 with total page 575 pages. Available in PDF, EPUB and Kindle. Book excerpt: Every 30 seconds a death is caused by Malaria. This book brings together recent advances in our understanding of the basic biology, genetics and pathogenesis of malaria, to facilitate the rapid generation of new insights and interventions. Each chapter is written by a leading expert(s), and serves as both a useful introduction to the area and a helpful set of references. Malaria: Parasite Biology, Pathogenesis and Protection is a useful entry point for graduate and medical students, scientists and individuals engaged in a subspecialty of Malaria research, as well as those who are simply interested in getting a grasp on the present status of this ever burgeoning public health problem.
