Development of transition state analogues of purine nucleoside phosphorylase as anti-T-cell agents.
Newborns with a genetic deficiency of purine nucleoside phosphorylase (PNP) are normal, but exhibit a specific T-cell immunodeficiency during the first years of development. All other cell and organ systems remain functional. The biological significance of human PNP is degradation of deoxyguanosine, and apoptosis of T-cells occurs as a consequence of the accumulation of deoxyguanosine in the circulation, and dGTP in the cells. Control of T-cell proliferation is desirable in T-cell cancers, autoimmune diseases, and tissue transplant rejection. The search for powerful inhibitors of PNP as anti-T-cell agents has culminated in the immucillins. These inhibitors have been developed from knowledge of the transition state structure for the reactions catalyzed by PNP, and inhibit with picomolar dissociation constants. Immucillin-H (Imm-H) causes deoxyguanosine-dependent apoptosis of rapidly dividing human T-cells, but not other cell types. Human T-cell leukemia cells, and stimulated normal T-cells are both highly sensitive to the combination of Imm-H to block PNP and deoxyguanosine. Deoxyguanosine is the cytotoxin, and Imm-H alone has low toxicity. Single doses of Imm-H to mice cause accumulation of deoxyguanosine in the blood, and its administration prolongs the life of immunodeficient mice in a human T-cell tissue xenograft model. Immucillins are capable of providing complete control of in vivo PNP levels and hold promise for treatment of proliferative T-cell disorders.
Schramm
Vern L
VL
Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forch. 308, Bronx, NY 10461, USA. vern@aecom.yu.edu
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015458:Leukemia, T-Cell / Q000188:drug therapy*; D051379:Mice; D009705:Nucleosides / Q000378:metabolism; D011684:Purine Nucleosides; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D055672:Static Electricity; D013601:T-Lymphocytes / Q000187:drug effects*; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009705:Nucleosides; D011684:Purine Nucleosides; D011744:Pyrimidinones; D011758:Pyrroles; C113101:forodesine; D011683:Purine-Nucleoside Phosphorylase