Research Project
2233560
Neutrophil recruitment to sites of inflammation is necessary for repair of damaged tissue, but in some instances the process may lead to further damage of the involved tissue. The action of Mac-1, an adhesion molecule expressed on the surface of neutrophils, is required for neutrophil recruitment during the inflammatory response. It may be therapeutically useful to inhibit the action of Mac-1 on neutrophils for the treatment of acute inflammatory conditions such as acute respiratory distress syndrome, stroke, inflammatory bowel disease, and ischemia-reperfusion injury. We have identified a peptide which inhibits Mac-1 mediated neutrophil adherence in vitro, with an IC5O of 2 micromoles. The goal of this Phase I study is to develop a more potent version of this Mac-1 antagonist through phage display. Libraries of filamentous phage will be generated which display mutated versions of the lead peptide as a fusion with a phage coat protein. The phage, which express peptides with high affinity for Mac-1 will be selected from the library by binding to purified Mac-1. Peptides identified by phage display will be synthesized and assayed in vitro for their ability to inhibit neutrophil adherence. PROPOSED COMMERCIAL APPLICATION: Peptide antagonists of Mac-1 will be useful in the treatment of acute inflammatory diseases by inhibiting neutrophil-mediated damage. A Mac-1 inhibitor has significant potential in the treatment of acute respiratory distress syndrome, stroke, inflammatory bowel disease, and ischemia-reperfusion injury.
