Targeting the Trypanosomatidae: Inhibitor development for nucleoside hydrolases and metacaspases

Sleeping sickness, Chagas' disease and leishmaniasis are caused by the unicellular parasites Trypanosoma brucei, Trypanosoma cruzi and different Leishmania species. These three parasitic diseases are grouped under the name 'most neglected diseases' and are responsible for infections in the poorest and most rural areas of Africa, South and Central America and parts of Asia. There is an urgent need for new chemotherapeutics, because most of the drugs available are old and limited in efficacy, plagued by severe side effects, poor patient compliance and harm-strung by drug resistance.;During this PhD work, the purine salvage pathway (PSP) and cysteine proteases were considered as target metabolic pathways for the design and development of antitrypanosomal drugs. The first target enzyme is the nucleoside hydrolase (NH), which is regarded as a key enzyme in the PSP. The second target enzyme is the newly discovered metacaspase (MCA) which belongs to the cysteine proteases. Both target enzymes of this PhD work are considered as viable targets for antiparasitic chemotherapeutics. The design, synthesis and biochemical evaluation of inhibitors of NHs and MCAs of Trypanosoma vivax and Trypanosoma brucei have been described.;Nucleoside hydrolase project. This research resulted in a promising antiparasitic compound with selective activity against T. b. brucei and T. b. rhodesiense. In vivo studies in a rodent model showed complete blood clearance after 10 days post infection (dpi) and a survival rate of 75% at 21 dpi. No cross-resistance with the diamidines nor the melaminophenyl arsenical compounds is expected, which is a prerequisite for its clinical consideration. It was hypothesized that this compound acts on an additional target besides the nucleoside hydrolase, because the collected data suggest that it is probably not sufficient to target only the nucleoside hydrolase activity to block the purine salvage pathway of T. b. brucei. Further in vivo studies are planned.;Metacaspase project. The first attempt for the development of inhibitors of T. brucei metacaspases resulted in a valuable lead compound with low micromolar enzymatic activity, modest antiparasitic activity, selectivity towards human caspase-3 and lack of cytotoxicity. These discoveries will be the onset for further optimisation efforts.