We study the biosynthetic pathways of nucleotides in Trypanosoma brucei, Giardia lamblia, Borrelia burgdorferi and other pathogens.
Nucleotides are needed as building blocks to manufacture DNA and RNA. Many pathogens lack important enzymes for nucleotide biosynthesis and are therefore dependent on nucleotide precursors (ribonucleosides, deoxynucleosides and bases), which can be taken up from the host organism. In the case of ribonucleosides and deoxynucleosides, they need to be phosphorylated in three steps before being usable as building blocks for RNA and DNA. We study the enzymes responsible for the first phosphorylating step.
Trypanosoma brucei is a unicellular parasite, which is spread by tsetse flies and causes the fatal disease African sleeping sickness. We exploit that the pathogen cannot perform de novo synthesis of adenosine (a ribonucleoside), which makes it dependent on the enzyme adenosine kinase to phosphorylate adenosine which is taken up from the blood. We exploit this weakness of the pathogen by developing substances (adenosine analogues), which resemble adenosine but kill the parasites after being activated by the enzyme.
The goal is to take advantage of the differences in the synthetic pathways in these pathogens compared to our own cells and thereby being able to identify drugs with minimized side effects.
Giardia lamblia and Borrelia burgdorferi are two pathogens that lack the enzyme ribonucleotide reductase and can therefore not make the building blocks needed for de novo DNA biosynthesis. It is then the DNA building blocks (deoxynucleosides) which need to be taken up from the surroundings and be phosphorylated. The pathogen Trichomonas vaginalis lacks many of the enzymes needed to synthesize building blocks for both RNA and DNA synthesis and we therefore study the enzymes needed for the phosphorylation of both ribonucleosides and deoxyribonucleosides. We develop false substrates of these enzymes which after activation harm the pathogens.
Giardia lamblia causes giardiasis, a severe diarrhea which can sometimes become fatal whereas Trichomonas vaginalis causes trichomoniasis, a venereal disease coupled to cervical cancer. The treatments of giardiasis, trichomonas and African sleeping sickness give side effects and in many cases the diseases are not cured by current treatments. Borrelia burgdorferi causes borreliosis. Thre treatment options against early stage borreliosis are better than against the other three diseases but with an increasing antibotic resistance there is also in this case a need to develop new drugs. In contrast to existing medicines, our substances are targeting unique features of the pathogens, and there is thereby no risk that the drug resistance can spread between different species.