inosinic-acid and forodesine

The proposed transition state for hypoxanthine-guanine phosphoribosyltransferases (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 (immucillinHP) and (1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate (immucillinGP) are the most powerful inhibitors yet reported for both human and malarial HGPRTs. Equilibrium binding constants are >1,000-fold 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. The inhibitors are lead compounds for species-specific antibiotics against parasitic protozoa. The high-resolution crystal structure of human HGPRT with immucillinGP is reported in the companion paper.

Topics: Animals; Binding Sites; Catalysis; Diphosphates; Drug Design; Enzyme Inhibitors; Guanosine Monophosphate; Humans; Hydrogen Bonding; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase; Inosine Monophosphate; Kinetics; Magnesium Compounds; Nuclear Magnetic Resonance, Biomolecular; Phosphoribosyl Pyrophosphate; Phosphorylation; Plasmodium falciparum; Protein Binding; Protons; Purine Nucleosides; Pyrimidinones; Pyrroles