Immucillins as antibiotics for T-cell proliferation and malaria.
The genetic deficiency of human PNP causes a specific immunodeficiency by inducing apoptosis in dividing T-cells. Powerful inhibitors of PNP have been designed from the experimental determination of the transition state structure of PNPs. The Immucillins are transition state analogue inhibitors with Kd values as low as 7 pM. In the presence of deoxyguanosine the Immucillins kill activated human T-cells but not other cell types. The Immucillins are orally available and of low toxicity to mice. Immucillins also inhibit PNP from Plasmodium falciparum. Parasites cultured in human erythrocytes are killed by purine starvation in the presence of Immucillins and can be rescued by hypoxanthine.
Schramm
Vern L
VL
Albert Einstein College of Medicine, Yeshiva University, Bronx, New York 10461, USA.
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D049109:Cell Proliferation; D003849:Deoxyguanosine / Q000737:chemistry; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D019271:Hypoxanthine / Q000378:metabolism; D007700:Kinetics; D008213:Lymphocyte Activation; D008288:Malaria / Q000097:blood*; D008956:Models, Chemical; D010641:Phenotype; D010963:Plasmodium falciparum / Q000378:metabolism; D011684:Purine Nucleosides; D011687:Purines / Q000737:chemistry; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology*
D000900:Anti-Bacterial Agents; D011684:Purine Nucleosides; D011687:Purines; D011744:Pyrimidinones; D011758:Pyrroles; D019271:Hypoxanthine; C113101:forodesine; D003849:Deoxyguanosine