We propose to use a combinatorial unrandomization technique to identify inhibitors of two human phospholipase A/2 (PLA/2) enzymes, type II and cytosolic. PLA/2-catalyzed hydrolysis of membrane phospholipids is the rate-limiting step in the production of a number of proinflammatory eicosanoids and production of the enzyme is regulated by proinflammatory cytokines. Thus, PLA/2 occupies a central position in the inflammatory cascade.
The aims of this proposal are to synthesize libraries of random oligomers from phosphoramidite monomers derivatized with diverse functional groups and to screen the libraries for inhibition of PLA/2 enzymatic activity. A unique compound will be identified using an iterative synthesis and screening approach. This combinatorial unrandomization technique that has been used to select a phosphorothioate inhibitor of HIV envelope-mediated cell fusion (Wyatt et al. Proc. Natl. Acad. Sci., 1994).
Initial use of PLA/2 inhibitors discovered through a combinatorial approach would be in topical treatment of psoriasis, atopic dermatitis, allergic rhinitis and other inflammatory disorders of the skin. Delivered systemically, the oligomers could be used to treat rheumatoid arthritis, inflammatory bowel disease and septic shock. Oligomers will effectively compete for part of the market currently occupied by glucocorticoids and non-steroidal anti-inflammatory agents.
