ABSTRACT
Purine nucleoside phosphorylase (PNP) catalyzes the reversible phosphorylysis of ribonucleosides and 2′-deoxyribonucleosides of guanine, hypoxanthine, and related nucleoside analogs. PNP isolated from human erythrocytes is specific for the 6-oxypurines and many of their analogs while PNPs from other organisms vary in their specificity. Interest in PNP as a drug target arises from its ability to rapidly metabolize purine nucleosides and from its role in the T-cell branch of the immune system. The PNP inhibitors alone have potential therapeutic value based on the importance of PNP to the immune system. Patients lacking PNP activity exhibit severe T-cell immunodeficiency while maintaining normal or exaggerated B-cell function. The carbon-for-nitrogen switch in the 9-deaza variant favors association with PNP by substituting a strong hydrogen bond for the relatively weak one occurring between Asn 243 and guanine. Scientists at BioCryst have successfully completed a project to design and synthesize potent inhibitors of the enzyme PNP using the three-dimensional structure of the active site.
