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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Inhibitors of the Enzyme Purine Nucleoside Phosphorylase as Potential Therapy for Psoriasis

Author(s): Philip E. Morris,Jr. and George A. Omura

Volume 6, Issue 9, 2000

Page: [943 - 959] Pages: 17

DOI: 10.2174/1381612003400083

Price: $65


Purine nucleoside phosphorylase (PNP) is one of the enzymes comprising the purine salvage pathway, and is responsible for the catalysis of the reversible phosphorolytic cleavage of purine ribonucleosides and 2-deoxyribonucleosides. The pivotal role of PNP in T-cell proliferation has been demonstrated in patients with inherited PNP deficiency, where T-cell levels may be 1-3percent of normal. This observation helped establish the critical role of PNP in T-cells and provided a rationale for developing inhibitors of PNP. Inhibitors of PNP may be useful for treating a variety of T-cell related autoimmune diseases including psoriasis, rheumatoid arthritis and Crohns disease and T-cell cancers. In this manuscript, the x-ray crystal structure of the PNP enzyme is described. Results of a structure-based drug design program aimed at designing small-molecule inhibitors of PNP are also described. Of the many classes of compounds synthesized, studied and reviewed, only one, the 3-pyridinylmethyl-9-deazaguanine (BCX-34, 39) analog has been used in clinical trials. Both topical and oral formulations of BCX-34 were studied in psoriatic patients and the results of these clinical trials are described.

Keywords: Enzyme Purine Nucleoside Phosphorylase, Human immunodeficiency virus, HIV, PNP enzyume, PNP inhibitors, X ray crystallographic analysis

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