DEVELOPMENT OF ANTISCHISTOSOMAL AGENTS - INHIBITORS OF HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE

Derivatives of purines and 5-phosphoribosyl 1-pyrophosphate (PRPP), substrates for purine salvage enzymes, were tested for their ability to inhibit hypoxanthine-guanine phosphoribosyltransferase (HPRT, E.C. 2.4.2.8) isolated from Schistosoma mansoni in vitro. The parasite enzyme exhibited different kinetic characteristics than the human enzyme. The -C2 and -C6 substituted purine derivatives, as well as PRPP-polyamine complexes, were found to be active against the enzyme. Intact purine ring appears to be necessary for the activity against the hypoxanthine dependent reactions mediated by the parasite enzyme since benzimidazoles, quinolines, and triazoles were found to be inactive. Additionally, it appears that PRPP-polyamine complexes which inhibit the PRPP dependent reaction may provide a novel approach to new chemotherapeutics agents for schistosomiasis.