II 8 Receptor Antagonists for Imaging and Therapy

Interleukin-8 (IL-8), a newly characterized proinflammatory cytokine, is chemotactic for polymorphoneutrophils (PMNs). It produces several other agonist effects, including granule release of degradatproduction of oxygen-derived free radicals. These effects are mediated by specific high affinity (Kd(IL-8R), which are expressed in high numbers on the PMN membrane surface. Our overall objective in tis to develop a potent and selective, small peptide IL-8R antagonist, which would have both diagnostpotential. To that end, we have several specific aims in Phase I: 1) synthesize by solid phase techncontaining portions of IL-8 that appear from previous studies to be critical in IL-8R binding and/orthese peptides for their ability to compete with 125I-labelled IL-8 for specific binding to IL-8Rs iPMN membranes; and 3) evaluate compounds demonstrating IL-8R binding affinity from #2 for their abilinduced PMN chemotaxis and elastase release by isolated PMNs. In Phase II lead compounds emanating fwill be evaluated in vivo for their utility as infection-imaging agents and in relevant animal modelPMNs and/or IL-8 are implicated.