Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes

Transition-state theory has led to the design of Immucillin-H (Imm-H), a pi comolar inhibitor of purine nucleoside phosphorylase (PNP). In humans, PNP is the only route for degradation of deoxyguanosine, and genetic deficiency of this enzyme leads to profound T cell-mediated immunosuppression. This s tudy reports the biological effects and mechanism of action of Imm-H on mal ignant T cell lines and on normal activated human peripheral T cells, Imm-H inhibits the growth of malignant T cell leukemia lines with the induction of apoptosis. Imm-H also inhibits activated normal human T cells after anti genic: stimulation in vitro. However, Imm-H did not inhibit malignant B cel ls, colon cancer cell lines, or normal human nonstimulated T cells, demonst rating the selective activity of Imm-H. The effects on leukemia cells were mediated by the cellular phosphorylation of deoxyguanosine and the accumula tion of dGTP, an inhibitor of ribonucleotide diphosphate reductase, Cells w ere protected from the toxic effects of Imm-H when deoxyguanosine was absen t or when deoxycytidine was present. Guanosine incorporation into nucleic a cids was selectively blocked by Imm-H with no effect on guanine, adenine, a denosine, or deoxycytidine incorporation. Imm-H may have clinical potential for treatment of human T cell leukemia and lymphoma and for other diseases characterized by abnormal activation of T lymphocytes. The design of Imm-H from an enzymatic transition-state analysis exemplifies a powerful approac h for developing high-affinity enzyme inhibitors with pharmacologic activit y.