Transition-state analogs as inhibitors of human and malarial hypoxanthine-guanine phosphoribosyltransferases

The proposed transition state for hypoxanthine-guanine phosphoribosyltransf erases (HGPRTs) has been used to design and synthesize powerful inhibitors that contain features of the transition state. The iminoribitols (1S)-1-(9- deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate (immucil linHP) and (1S)-1-(9-deazaguanin-9-yl)-1 4-dideoxy-1,4-imino-D-ribitol 5-ph osphate (immucillinGP) a re the most powerful inhibitors yet reported for b oth human and malarial HGPRTs. Equilibrium binding constants are >1,000-fol d tighter than the binding of the nucleotide substrate. The NMR spectrum of malaria HGXPRT in the Michaelis complex reveals downfield hydrogen-bonded protons. The chemical shifts move farther downfield with bound inhibitor. T he inhibitors are lead compounds for species-specific antibiotics against p arasitic protozoa. The high-resolution crystal structure of human HGPRT wit h immucillinGP is reported in the companion paper.