TY - JOUR
T1 - Development of transition state analogues of purine nucleoside phosphorylase as anti-T-cell agents
AU - Schramm, Vern L.
N1 - Funding Information:
Research in this laboratory is supported by research grants from the National Institutes of Health. Greg Kicska and Robert Miles have been instrumental in the research on PNP and Imm-H in this laboratory. Alexander Fedorov, Wuxian Shi and Steven Almo are responsible for the X-ray crystallography. Richard Furneaux and Peter Tyler of Industrial Research, New Zealand, pioneered the synthesis of Imm-H, and Shanta Bantia of BioCryst has had a central role in cellular and animal studies. The author thanks Brett Lewis for help in preparing figures.
PY - 2002/7/18
Y1 - 2002/7/18
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Autoimmunity
KW - Deoxyguanosine toxicity
KW - Immucillin
KW - Purine nucleoside phosphorylase
KW - T-cell leukemia
KW - Transition state
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U2 - 10.1016/S0925-4439(02)00073-X
DO - 10.1016/S0925-4439(02)00073-X
M3 - Review article
C2 - 12084452
AN - SCOPUS:0037130281
SN - 0925-4439
VL - 1587
SP - 107
EP - 117
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 2-3
ER -