BIOCHEMISTRY OF TRYPANOSOMATIDS--BASIS FOR DRUG DESIGN

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Utilizing trypanosomes as a model parasite, we have defined a biochemical difference between the host and the parasite which is ideal as a choice for the design of new trypanocidal agents. The basis of this difference lies in the sensitivity of trypanosomes to oxidant stress while the mammalian host has adequate and multiple defense mechanisms. In the current application, we propose to study two aspects in depth. These include a means of generating oxygen free radicals in the trypanosome in vivo and a way of decreasing the ability of the trypanosome to withstand indogenous or exogenous oxidant stress by interferring with the maintenance of reduced glutathione. Preliminary evidence points to the ability of a number of quinones to generate superoxide and hydrogen peroxide which can lyse trypanosomes in vitro. Many of these new agents are lytic in the micromolar range; however, only one has displayed any trypanocidal activity in vivo. The lack of activity in vivo, reflects the rapid clearance and metabolism by the mammalian host. Quinones appear to readily react by Michael addition to proteins and be inactivated. The one agent, 2,3 bis-(guanylhydrozone butyl)-1,4 naphthoquinone that retained partial biological activity in vivo points to the possibility of designing new agents which can avoid metabolism by the mammalian host while retaining trypanocidal activity. The rationale and the synthetic routes for a number of these new derivatives are described. The second point of attack to be evaluated is the enzyme glutathione reductase. This enzyme which is responsible for the regeneration of reduced glutathione from oxidized glutathione has not previously been isolated from trypanosomes. It is proposed that this enzyme be isolated, characterized and compared with the mammalian enzyme. In addition, the synthesis of the number of new agents which could interact with the active site of the enzyme will be undertaken. Emphasis will be placed on finding analogs which are more favorably positioned for reaction in the active site of the trypanosome enzyme than in the mammalian enzyme. These studies, hopefully, will lead to the identification of a compound which will contain a nonmetalic di-thiol acceptor which will replace the arsenic moiety of molarsenoxide.