Design of novel trypanocide drugs

Abstract

American Trypanosomiasis or Chagas disease, described by Carlos Chagas in 1909 in this Country, is caused by a flagellate protozoan parasite, Trypanosoma cruzi. Trypanocidal drugs have been used in the treatment of Chagas disease since the 1960s, when nitrofurans and later imidazolic drugs were introduced in the clinics. But efficacy is not so good. Current drug therapies are plagued by such problems as resistance and toxicity to the patient Therefore, the potential of trypanocidal therapy to prevent Chagas' disease remains to be evaluated. The closely related trypanosomatids of genus Leishmania are also the causative agents of a variety of diseases collectively known as leishmaniases. Drugs used to treat leishmaniases are also hampered by the same problems associated with side effects and resistance. Trypanosomatids are highly dependent on glycolysis as a source of ATP production and compounds which inhibit glycolysis have been shown to be trypanocidal. The structures of glycosomal enzymes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from the trypanosomatid parasites T. cruzi and L. mexicana have been determined by X-ray crystallography. The structure of L. mexicana GAPDH is very similar to that of T. cruzi, but structural differences between trypanosomatid and human GAPDH allow for selectively inhibiting the trypanosomatid isozyme. In the search for more effective trypanocidal drugs, this project is intended at working on (i) ligand-based and target-based drug design to encompass (ii) generation of template molecules for further decoration (iii) chemical screening by mass spectrometry (iv) experimental determination of partition coefficient related to permeability by the use of immobilized artificial membranes (v) determination of the thermodynamic signature of bioactive compounds by biocalorimetry. The integration of pharmacodynamics and pharmacokinetics is of paramount importance in all stages of drug discovery and development. In silico and molecular modeling provide such integration since the beginning of the medicinal chemistry project. (AU)