L-Enantiomers of Transition State Analogue Inhibitors Bound to Human Purine Nucleoside Phosphorylase

摘要

Human purine nucleoside phosphorylase (PNP) is required for degradation of 2'-deoxyguanosine and its genetic deficiency is characterized by a lethal T-cell immune deficiency caused by accumulation of dGTP in dividing T-cells. Human PNP is therefore a target for T-cell disease. The Immucillin family of transition state analogue inhibitors for PNP was developed based on experimentally measured kinetic isotope effects.3 Immucillin-H (ImmH) (1) and DADMe-Immucillin-H (DADMe-ImmH) (3) are picomolar inhibitors of PNP and are in clinical trials for T-cell malignancies and T-cell-based autoimmune diseases.