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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.
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