Interleukin-8 Receptor Antagonist: A Potential Infection-Imaging Agent and Therapeutic

Interleukin-8 (IL-8), a newly characterized proinflammatory cytokine, is chemotactic for polymorphonuclear neutrophils (PMNs) and stimulates several other agonist effects, all culminating in accumulation at the site of infection or inflammation and the full plethora of effects, including tissue injury via degradative enzymes and oxygen-derived free radicals. All of these effects are mediated by specific high affinity (Kd=10pM) 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 diagnostic and therapeutic potential (see below). To that end, our specific aims in Phase I are to: 1) synthesize by solid phase techniques 15 to 20 peptides containing those portions of IL-8 that appear from previous studies to be critical in IL-8R binding and/or activity; 2) examine all of these peptides for their ability to compete with I-labelled IL-8 for specific binding to IL-8Rs in isolated human PMNs or PMN membranes; and 3) evluate 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 evlauated 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. Anticipated Benefits: 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 potentn, specific IL-8R antagonist also would have wide therapeutic utility in many diseases/conditions such as adult respiratory distress syndrome, myocardial infarction, cystic fibrosis, psoriasis, and septic shock.