Inhibitors of the enzyme purine nucleoside phosphorylase

Abstract

The enzyme purine nucleoside phosphorylase (PNP) catalyses the reversible cleavage of purine nucleosides to the purine base and ribose-1-phosphate. Several cases of a rare genetic disorder in which PNP is lacking have been reported in children. These children were found to be T-cell immunodeficient while their B-cell immunity remained normal. This observation helped establish the relationship between PNP and T-cells and provided the impetus for the development of inhibitors of PNP which may be useful for the treatment of T-cell proliferative disorders. Proliferating T-cells have been implicated in cutaneous T-cell lymphoma and in T-cell leukaemias. Autoimmune diseases such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, Crohn’s disease and Type I diabetes are also thought to be T-cell mediated. Other diseases which may benefit from treatment with PNP inhibitors are gout and infection from human immunodeficiency virus (HIV). The half-life of nucleoside antivirals may also be increased by co-administration with a PNP inhibitor. The therapeutic potential for PNP inhibitors has been clearly established and several classes of PNP inhibitors have been described in the literature. Despite the number of potent inhibitors known, only one has reached advanced clinical trials.

• autoimmune disease
• deazaguanine
• guanine
• PNP inhibitor
• purine nucleoside phosphorylase
• structure-based drug design
• T-cell proliferative diseases