Iminoribitol transition state analogue inhibitors of protozoan nucleoside hydrolases

Nucleoside N-ribohydrolases from protozoan parasites are targets for inhibi tor design in these purine-auxotrophic organisms. Purine-specific and purin e/pyrimidine-nonspecific nucleoside hydrolases have been reported. Iminorib itols that are 1-substituted with meta- and para-derivatized phenyl groups [(1S)-substituted 1,4-dideoxy-1,4-imino-D-ribitols] are powerful inhibitors for the nonspecific nucleoside N-ribohydrolases, but are weak inhibitors f or purine-specific isozymes [Parkin, D. W., Limberg, G., Tyler, P. C., Furn eaux, R. H., Chen, X.-Y., and Schramm, V. L. (1997) Biochemisty 36, 3528-35 34]. Binding of these inhibitors to nonspecific nucleoside hydrolase occurs primarily via interaction with the iminoribitol, a ribooxocarbenium ion an alogue of the transition state. Weaker interactions arise from hydrophobic interactions between the phenyl group and the purine/pyrimidine site. In co ntrast, the purine-specific enzymes obtain equal catalytic potential from l eaving group activation and ribooxocarbenium ion formation. Knowledge of th e reaction mechanisms and transition states for these enzymes has guided th e design of isozyme-specific transition state analogue inhibitors. New synt hetic efforts have produced novel inhibitors that incorporate features of t he leaving group hydrogen-bonding sites while retaining the iminoribitol gr oup. These compounds provide the first transition state analogue inhibitors for purine-specific nucleoside hydrolase. The most inhibitory I-substitute d iminoribitol heterocycle is a sub-nanomolar inhibitor for the purine-spec ific nucleoside hydrolase from Trypanosoma brucei brucei. Novel nanomolar i nhibitors are also described for the nonspecific nucleoside hydrolase from Crithidia fasciculata. The compounds reported here are the most powerful im inoribitol inhibitors yet described for the nucleoside hydrolases.