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Malaria
The first decade of the 21st century has been met with many successes as well as disappointments in the area of malaria control. From a scientific research perspective the achievements have been extraordinary and include developments such as 1) the sequencing of the Plasmodium falciparum (causative parasite) [1] and Anopheles gambiae (insect vector) [2] genomes; which has resulted in 2) the development of vast, freely available databases such as PlasmoDB [3]; 3) the release of the transcriptomic [4-7], proteomic [8,9] and metabolomic [10] profiles of the intra-erythrocytic infectious stages of the parasite within the human host; and 4) the promising results of the RTS,S/AS vaccine against falciparum malaria, which is currently in phase III clinical trials [11]. In terms of vector control, the WHO has revised the use of DDT (bis(4- chlorophenyl)-1,1,1-trichloroethane) in 2006 as a means to control the transmission of malaria by mosquitoes (http://www.who.int/whopes/), despite the resistance met from environmental protection agencies [12]. The creation of transgenic mosquitoes has also received attention in the scientific community to reduce the capacity of parasites to infect humans [13].
The 2010 World Malaria Report (WHO 2010) stated that nearly 289 million insecticide-treated mosquito nets (ITNs) were delivered to sub-Saharan Africa between 2008 and 2010, which conferred malaria transmission protection to 578 million people, including children and pregnant women (http://www.who.int/malaria/world_malaria_report_2010/). In 2009, 75 million Africans were also protected by indoor residual spraying (IRS) and these preventative efforts have resulted in measurable effects on public health as follows: 1) the number of malaria cases decreased from 244 million in 2005 to 225 million in 2009 (~7%); 2) the number of deaths decreased from 985 000 in 2000 to 781 000 in 2009 (~20%); 3) the number of countries that have reduced their malaria burden by 50% over the past decade continues to rise resulting in fewer countries that are endemic for malaria; and 4) in 2009 not a single case of cerebral malaria was reported in the WHO European Region. The decrease in malaria deaths can be attributed to improved access to treatment, vector control measures and diagnostic testing, which is reflected in the fact that most cases of fever in Africa are no longer due to malaria infection and the availability of inexpensive, easy-to-use, quality-assured rapid diagnostic tests for this disease (WHO 2010). Despite these successes, malaria resurgence is still observed in some African countries and even though funding for malaria control has increased dramatically in recent years (from $592 million in 2006 to over $1 billion in 2008, and $1.7 billion in 2009). The Roll Back Malaria Partnership estimates that $5.2-6 billion is required per annum in order to achieve the targets by 2015 that have been set by the Global Malaria Action Plan. Furthermore, the current global economic recession is likely to decrease aid as reflected by the 5-10% cut in the USA science and technology budget for 2011 and 2012, which makes malaria funding uncertain.
The chief disappointment with regards to malaria control remains the ongoing development of parasite resistance, which has rendered several antimalarial medicines ineffective especially in the parts of the world where malaria remains cataclysmic. The most dreadful being the resistance threats of the most promising and highly effective artemisinin derivatives, which was confirmed at the Cambodia-Thailand border in 2009 [14]. However, despite the observed changes in parasite sensitivity to artemisinins, ACT (artemisinin-based combination therapy) remains in effect and has been combined with efforts to limit the spread of resistant parasites. Another alarming event observed in the last decade was the inclusion of P. knowlesi, common in macaque monkeys, as the fifth species than can cause malaria in humans [15].
More than 40% of the world’s population reside in areas where they are at risk of malaria transmission (Figure 1.1, upper panel). Most deaths due to malaria occur in Africa, which is also one of the poorest regions of the world (Figure 1.1, lower panel). The disease contributes to poor economic growth, which has a further negative impact on malaria treatment and prevention. Malaria is a complicated disease and its spread may be attributable to a variety of factors such as ecological and socio-economic conditions, displacement of large population groups, agricultural malpractices causing an increase in vector breeding, global warming, parasite resistance to antimalarial drugs and vector resistance to insecticides.
A number of promising antimalarial drug and vaccine discovery projects have been launched. This includes the Medicines for Malaria Venture (MMV, http://www.mmv.org/) funded by a number of organisations including the Bill and Melinda Gates Foundation (http://www.gatesfoundatiojn.org/) for the development of novel antimalarials. The identification of new drug targets for malaria chemotherapeutic development is an ongoing process and is dependent on the study of disease pathology, parasite invasion and immune defence strategies, parasite transmission as well as parasite growth and development.
Chapter 1 Introduction .
1.1. Malaria
1.1.1. The P. falciparum life cycle
1.2. Treating malaria
1.2.1. Vector control
1.2.3. Current antimalarials .
1.3. Novel antimalarial targets
1.4. Research objectives
1.5. Outputs .
2. Chapter 2 A conserved parasite-specific insert is a key regulator of the activities and interdomain interactions of Plasmodium falciparum AdoMetDC/ODC
2.1. Introduction
2.2. Methods
2.3. Results
2.4. Discussion
2.5. Conclusion
3. Chapter 3: Biochemical and structural characterisation of monofunctional Plasmodium falciparum AdoMetDC
3.1. Introduction .
3.2. Methods
3.3. Results .
3.4. Discussion
3.5. Conclusion
4. Chapter 4:Validation of pharmacophore-identified inhibitors against Plasmodium falciparum SpdS with X-ray crystallography
4.1. Introduction
4.1.1. Identification of novel compounds against PfSpdS with the use of a dynamic
pharmacophore model .
4.2. Methods
