Grant: Collaborative Health Research Projects

Peptides are important molecules for drug discovery, but inherent properties such as poor bioavailability and rapid disposal handicap their clinical use. These drawbacks have however been surmounted using approaches such as cyclization and azapeptides. Combing the latter two methods, we have conceived an effective protocol for making cyclic azapeptides (azacyclopeptides) that demonstrate remarkable attributes for drug development. Macrophages are an important class of white blood cells that recognize damaged and foreign substances (e.g., cellular debris, microbes and cancer cells) which they engulf and digest in a process called phagocytosis, that triggers signaling pathways leading to inflammation. Macrophage response to oxidized lipids, lipoproteins and their degradation products is central for maintaining healthy tissue. During disease states, such as macular degeneration, however, pronounced macrophage function can aggravate inflamed tissue by creating reactive oxygen species and amplifying inflammation thus causing further tissue damage. Molecules that can modulate macrophage activity are pertinent targets due to their potential to enhance clearance of cellular debris without generating reactive oxygen species and accrued inflammatory factors. Targeting the CD36 scavenger receptor, which is commonly found on the surface of macrophages and integrally engaged in the absorption of oxidized lipid and lipoprotein debris, we have conceived cyclic azapeptides that can modulate the inflammatory response to favor clearance without production of reactive oxygen species. Central to the proposed research will be the further optimization and use of the cyclic azapeptides to mitigate the causes of age-related macular degeneration, the leading cause of adult vision loss by modulating macrophage-mediated inflammation.