Meng-Chiao Ho, Wuxian Shi, Agnes Rinaldo-Matthis, Peter C Tyler, Gary B Evans, Keith Clinch, Steven C Almo, Vern L Schramm
Inhibition of human purine nucleoside phosphorylase (PNP) stops growth of activated T-cells and the formation of 6-oxypurine bases, making it a target for leukemia, autoimmune disorders, and gout. Four generations of ribocation transition-state mimics bound to PNP are structurally characterized. Immucillin-H (K*i(1/4) 58 pM, first generation)contains an iminoribitol cation with four asymmetric carbons. DADMe-Immucillin-H (K*i(1/4) 9 pM, second-generation),uses a methylene-bridged dihydroxypyrrolidine cation with twoasymmetric centers...
March 16, 2010: Proceedings of the National Academy of Sciences of the United States of America