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Document 5 Design of Purine Nucleoside Phosphorylase Inhibitors Y. Sudhakara Babu, John A. Montgomery, and Charles E. Bugg BioCryst Pharmaceuticals, Inc., Birmingham, Alabama W. Michael Carson, Sthanam V. L. Narayana, and William J. Cook The University of Alabama at Birmingham, Birmingham, Alabama Steven E. Ealick Cornell University, Ithaca, New York Wayne C. Guida and Mark D. Erion * Ciba-Geigy Corporation, Summit, New Jersey John A. Secrist, III Southern Research Institute, Birmingham, Alabama I. Introduction A. Enzymology Page 151 Purine nucleoside phosphorylase (PNP, E.C. 2.4.2.1) catalyzes the reversible phosphorylysis of ribonucleosides and 2'-deoxyribonucleosides of guanine, hypoxanthine, and related nucleoside analogs [1]. It normally acts in the phosphorolytic direction in intact cells, although the isolated enzyme catalyzes the nucleoside synthesis under equilibrium conditions. Figure 1 shows the chemical reaction. The enzyme has been isolated from both eukaryotic and prokaryotic organisms [2] and functions in the purine salvage pathway [1,3]. Purine nucleoside phosphorylase isolated from human erythrocytes is specific for the 6-oxypurines and many of their analogs [4] while PNPs from other organisms vary in their specificity [5]. The human enzyme is a trimer with identical subunits and a total molecular mass of about 97,000 daltons [6,7]. Each subunit contains 289 amino acid residues. * Current affiliation: Gensia, Inc., San Diego, California. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_151.html [4/5/2004 5:01:07 PM]
Document B. Pharmacology Figure 1 The reaction catalyzed by PNP. Page 152 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. Unfortunately, PNP can also cleave certain anticancer and antiviral agents that are synthetic mimics of natural purine nucleosides, thus interfering with therapy. One such substance is ddI (2'3'-dideoxyinosine), which the Food and Drug Administration approved as a treatment for AIDS in 1991. Another is the potential anticancer agent 2'-deoxy-6thioguanosine [8]. Our goal was to develop a compound that when administered with the nucleoside analogs would inhibit PNP while the anticancer and antiviral agents accomplished their therapeutic missions. The combination of purine nucleoside analogs and a PNP inhibitor might prove to be a more effective treatment. 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 [9]. We, like other researchers, quickly recognized that PNP inhibitors might selectively suppress the T-cell proliferation associated with an array of autoimmune disorders such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus, multiple sclerosis, and insulin-dependent (juvenile-onset) diabetes [10]. This profile also suggests that PNP inhibitors might be useful in the treatment of T-cell proliferative diseases—such as T-cell leukemia or Tcell lymphoma—and in the prevention of organ transplant rejection. C. Drug Design Strategy Recent advances in biotechnology, macromolecular crystallography, computer graphics, and related fields have led to a new approach in drug discovery called structure-based drug design. Structure-based drug design requires a detailed structural knowledge of the target (enzyme or receptor) and the interaction of small molecules with it. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_152.html [4/5/2004 5:01:10 PM]
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Page 139 and 140: Document cubation of phosphotyrosin
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Page 149 and 150: Document 4 Bradykinin Receptor Anta
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