IngentaConnect Inhibitors of the Enzyme Purine Nucleoside Phosphorylase as Poten...

Authors: MorrisJr., P.E.; Omura, G.A.

Source: Current Pharmaceutical Design, Volume 6, Number 9, 1 June 2000 , pp. 943-959(17)

Publisher: Bentham Science Publishers

Abstract:

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.

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