Our approach is to exploit the diversity of the murine immune system to generate antibodies with phosphodiesterase activity. Specifically, we use a charged hapten that elicits a complementary charged residue in the antibody-combining site during the evolutionary timescale of immunization. Yet, adaptation of a series of complex reactions from solution to solid-phase synthesis is still in early development. Indeed, polymer-supported total synthesis of natural products has only recently been successful. The prostaglandin family of natural products contains perhaps the most physiologically potent nonprotein molecules found in mammals.
Prostaglandins play a vital role in inflammation, tissue repair, and the immune response.
Their complex structure and delicate framework have provided a benchmark for chemists interested in demonstrating new synthetic strategies. From a combinatorial standpoint, polymer-supported synthesis of such molecules ushers in another degree of complexity to the synthetic scheme. Although screening large numbers of such compounds would greatly improve the probability of finding appropriate biological activity, we are using novel soluble polymers to synthesize these complex molecules in a combinatorial format. Our reasoning is based on ease of purification and flexibility of these supports to adapt to a variety of chemical reactions. Figure 2 shows a prostaglandin E 2 scaffold that we used to synthesize a library of prostaglandin molecules on soluble polymer supports.