Azacyclopeptide Modulators of Immuno-metabolism to Treat Age-Related Macular Degeneration

氮杂环肽免疫代谢调节剂治疗年龄相关性黄斑变性

• 批准号: 538816-2019
• 负责人: Lubell, William
• 金额: $ 20.77万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Collaborative Health Research Projects
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=698150
• 关键词: Azacyclopeptide; Modulators; Immuno; metabolism; Treat

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.

多肽是药物发现的重要分子，但其固有的生物利用度差、处理速度快等特性阻碍了其临床应用。然而，这些缺点已经通过环化和氮肽等方法得到克服。结合后两种方法，我们设想了一种有效的合成环氮肽的方案