Polyamine Pathway as Drug Target against Malaria

Abstract: Popular Abstract in English An algae that has lost its ability to do photosynthesis over the last million years and started to feed on human blood causes about 600.000 death every year, a number equals about 8 times Lund’s present population. This evolved algae named Plasmod- ium falciparum causes Malaria, a tropical disease mainly affecting economically weak regions in Africa. Unlike bacteria or viruses, Plasmodium is an eukaryotic organism as humans are, but it lives as a single cell. This parasite has a very complex biology that is poorly understood today but it is known to evolve rapidly. Its fast adaptation to the environment is problematic for the fight against Malaria, since it gains resis- tances against effective antimalarials very fast. In 2014 reports of resistances against the most powerful antimalaria drug today, artemisinin, are a big warning sign that we might lose the fight against the disease if new drugs are not found soon. But how can we find new drugs? In the last century most drugs against malaria were extracts or isolated compounds from plants. Research developments in the last decades allows the design of drugs against a specific target of the pathogen. These targets are mainly enzymes, the working horses of every cell that are running the metabolism. Enzymes catalyze specific reactions in metabolic pathways and are large polymers of up to thousands of amino acids. They also have a three dimensional structure that is required for their function and the structure can be visualized by x-ray crystallography, but it requires the growth of protein crystals which is a difficult process in some cases. Knowing the structure, molecules can be designed that bind to that enzyme and potentially inhibit it and eventually kill the parasite. Two plasmodial enzymes and potential drug targets S-adenosylmethionine decar- boxylase (AdoMetDC) and spermidine synthase (SpdS) that are involved in the syn- thesis of small molecules called polyamines that are important for cell growth of the parasite are the subjects of this thesis work. AdoMetDC has several features that are typical for malarial proteins and are associated with the organism’s fast evolution. This enzyme is about 50 % longer than the equivalent in other organisms due to so called ’amino acid insertions’. In this thesis a variety of biochemical and biophysical studies provide new insights into possible evolution and structure of these insertions and the AdoMetDC enzyme itself that might apply for other plasmodial enzymes. The second enzyme, SpdS has a known crystal structure and the design of inhibitors that are specific for this enzyme is one focus of the present work. Conventional methods to find new inhibitors using computational screenings have a very low success rate, but studies on the mechanism presented here on how this enzyme binds its ligands provide a new strategy to find potential drugs.