Interleukin-8 (IL-8), a newly characterized proinflammatory cytokine, is chemotactic for polymorphonuclear neutrophils (PMNs). It produces several other agonist effects, including granule release of degradative enzymes and production of oxygen-derived free radicals. These effects are mediated by specific high affinity (Kd=10 pM) IL-8 receptors (IL-8R), which are expressed in high numbers on the PMN membrane surface. Our overall objective in this Phase I project is to develop a potent and selective, small peptide IL-8R antagonist, which would have both diagnostic and therapeutic potential. To that end, our specific aims in Phase I are to: 1) synthesize by solid phase techniques 15 to 20 peptides containing portions of IL-8 that appear from previous studies to be critical in IL-8R binding and/or activity; 2) examine these peptides for their ability to compete with 125I-labelled IL-8 for specific binding to IL-8Rs in isolated human PMNs or PMN membranes; and 3) evaluate compounds demonstrating IL-8R binding affinity from #2 for their ability to block IL-8-induced PMN chemotaxis and elastase release by isolated PMNs. In Phase II lead compounds emanating from this effort will be evaluated in vivo for their utility as infection-imaging agents and in relevant animal models of disease in which PMNs and/or IL-8 are implicated.
The rapid, definitive diagnosis of occult infections remains a medical problem with major economic and health consequences. A Technetium-99m-labelled IL-8R antagonist would have great medical and commercial potential for localizing infections noninvasively. A potent, specific IL-8R antagonist also would have therapeutic utility in several diseases or syndromes, such as adult respiratory distress syndrome, myocardial infarction, inflammatory bowel disease, cystic fibrosis, psoriasis, and septic shock.
