Project topics and materials
Get Complete Project Material File(s) Now! »
The control of malaria
Efforts to control malaria have employed a three-pronged approach involving drug development, vector control and vaccine development, applied separately or in combination (Bathurst and Hentschel, 2006). For example, by combining therapeutic strategies (e.g. the WHO recommends artemisinin-based combination treatments, ACT’s) and widespread use of bed nets (vector control), the malaria cases in Rwanda decreased by more than 50% (Enserink, 2010b). It has also been postulated that pre-erythrocytic stage vaccines as well as transmission blocking vaccines could be extremely effective in reducing the disease burden (Kappe et al., 2010). Although malarial infections can be reduced by the use of insecticidetreated bed nets and vector control, the absence of an efficient vaccine means that lifethreatening infections, which can only be treated by drugs, still occur at an alarming rate (Bathurst and Hentschel, 2006). Although the RTS,S/AS01E vaccine, based on the circumsporozoite protein of P. falciparum, has had promising results, providing protection after 15 months following administration (Lemnge et al., 2011), this vaccine is not yet in general use.
Several biological processes of the parasite have been targeted chemotherapeutically, but unfortunately, resistance has emerged against the majority of the available anti-malarial drugs, highlighting the urgent need for alternative therapies in the near future (Table 1.1) (Müller and Hyde, 2010). For example, resistance to the once widely-used anti-malarial drug chloroquine has become widespread. Chloroquine resistance arises as a result of mutations in the gene encoding PfCRT (the P. falciparum chloroquine-resistance transporter) (Martin et al., 2009b). A lysine to threonine mutation at position 76 in the protein allows chloroquine, which usually accumulates in the parasite’s acidic food vacuole, to exit the organelle and hence away from its primary site of action (Martin et al., 2009b). Current efforts in the development and discovery of novel anti-malarials is being coordinated through several research networks e.g. European Union sponsored Antimal (FP6 network, www.antimal.eu) and the South African Malaria Initiative (www.sami.org.za), as well as international partnerships such as the Medicines for Malaria Venture (MMV, www.mmv.org). The stated goal of MMV is: ‘…to reduce the burden of malaria in disease-endemic countries by discovering, developing and facilitating delivery of new, effective and affordable anti-malarial drugs.’ Several new drugs are under investigation within the MMV portfolio, including mini-portfolios where compound libraries are being screened from e.g. GlaxoSmithKline (Fig. 1.3).
Despite these efforts and increasing funding investments, no chemically novel entity has entered phase IIb clinical trials or drug development stages, and it is only artemisininderivatives combination therapies (e.g. CoArtem: arthemether-lumefantrine and ASAQ: artesunate-amodiaquine) that are in phase IV trials (www.mmv.org). Nevertheless, several new chemotypes are under investigation, with peroxides (OZ439), carboxiimides (GSK MP), imidazolepyrazines and pyrrolindines (Novartis) in early stage development (Fig. 1.3). New drug targets are also being identified. Within the MMV portfolio, inhibitors for dihydroorotate dehydrogenase and the kinases are actively being investigated and there are nine other projects that may well deliver new leads in the near future (www.mmv.org).
Chapter 1: Literature review
1.1 Malaria
1.1.1 General
1.1.2 Lifecycle of P. falciparum
1.1.3 The control of malaria
1.2 Polyamine metabolism
1.3 Membrane transport
1.4 Polyamine transport
1.5 Transport of solutes in intra-erythrocytic P. falciparum parasites
1.6 Objective
2 Chapter 2: Polyamine uptake by the intra-erythrocytic malaria parasite,P. falciparum.
2.1 Introduction
2.2 Materials and methods .
2.2.1 HEPES buffered solutions.
2.2.2 Cell culture and preparation .
2.2.3 Radioisotope uptake measurements
2.2.4 Creating RBCs with modified haemoglobin content
2.2.5 Cytosolic pH measurements of isolated P. falciparum parasites
2.2.6 Data analysis
2.3 Results ..
2.4 Discussion
3 Chapter 3: The effect of anthracene-polyamine conjugates on intraerythrocytic
3.1 Introduction
3.2 Materials and methods
3.3 Results
