THE RATIONAL DESIGN OF NEW DRUGS FOR SLEEPING SICKNESS

In the Trypanosomatidae, contrary to all other organisms, the glycolytic enzymes are located inside a microbody-like organelle called glycosome. these glycosomal enzymes play an essential role in the energy metabolism of the parasites, and because of their unique location in the cell they are attractive targets for new chemotherapeutic approaches. Most of the glycosomal enzymes and several of their cytosolic isoenzymes from Trypanosoma brucei and Leishmania mexicana have been purified to homogeneity or have been over-expressed. Two of the glycosomal enzymes have been crystallized and their three-dimensional structure solved. some characteristics common to the majority of the glycosomal enzymes and absent from all other glycolytic enzymes have been identified and studied. One typical aspect is the existence of unique peptide insertions or of N- and C-terminal extensions in the glycosomal proteins. These peptides are often characterized by and abundance of the positively charged amino acids: arginine and lysine. Three-dimensional modelling has revealed that these positively charged amino acids cluster on the surface of the proteins in two so-called hot spots that are about 40 Angstrom apart. Another important structural difference has been found in the NAD-binding region of the glycosomal glyceraldehyde-phosphate dehydrogenase. We have exploited some of these differences and this has resulted in the synthesis of compounds that specifically inhibit glycosomal enzymes and leave the glycolytic enzymes from other organisms unharmed.