Chemotherapy for diseases caused by hemoflagellate protozoa is hampered by the toxicity of most agents in current use and by the widespread occurrence of drug resistance. The search for novel, nontoxic agents based on biochemical lesions in these parasites is an important priority which has been neglected because of economic considerations. The basis of this proposal is the rational development of a newly discovered class of compounds with in vitro and in vivo trypanocidal activity. These compounds are analogs of 5'-deoxy-5'-(methylthio)adenosine (MTA), a byproduct of polyamine biosynthesis. The most effective of these compounds, 5'-deoxy-5'-(hydroxyethylthio)adenosine (HETA) is preferentially cleaved by trypanosome but not mammalian MTA phosphorylase into adenine + a ribose-l-phosphate analog which is believed to interfere with methionine metabolism in the parasite. HETA will serve as the lead compound for the design and synthesis of a series of HETA analogs with potentially enhanced trypanocidal activity. These proposed HETA analogs will be evaluated for their in vitro and in vivo efficacy against model infections of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense, with special attention to the identification of analogs with activity against drug resistant clinical isolates and central nervous system infections induced by trypanosomes. Analogs will also be screened for their in vitro effects against the related pathogens, Trypanosoma cruzi and Leishmania donovani. The biochemical mechanisms responsible for the selective trypanocidal activity of HETA and related analogs will also be investigated. Strategies to optimize the drug delivery characteristics of HETA and related analogs will include the synthesis of prodrug forms designed to release HETA slowly within the biological milieu. Overall, these studies are directed towards the selection of those HETA analogs with the most promising spectrum of trypanocidal and antileishmanial effects for further pharmacological development as antiparasitic agents.
