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

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方案来制造环氮杂环肽（氮杂环肽），它在药物开发中表现出显着的属性。巨噬细胞是一类重要的白细胞，它们能识别受损和外来物质（如细胞碎片、微生物和癌细胞），并在吞噬作用中吞噬和消化这些物质，从而触发导致炎症的信号通路。巨噬细胞对氧化脂质、脂蛋白及其降解产物的反应是维持健康组织的核心。然而，在黄斑变性等疾病状态下，巨噬细胞的显著功能可通过产生活性氧和放大炎症而加重炎症组织，从而导致进一步的组织损伤。调节巨噬细胞活性的分子是相关的靶标，因为它们有可能在不产生活性氧和累积炎症因子的情况下增强细胞碎片的清除。CD36清除受体通常存在于巨噬细胞表面，并参与氧化脂质和脂蛋白碎片的吸收，我们设想了可以调节炎症反应以促进清除而不产生活性氧的环氮肽。该研究的核心将是进一步优化和使用环氮肽，通过调节巨噬细胞介导的炎症来减轻年龄相关性黄斑变性的原因，黄斑变性是成人视力丧失的主要原因。

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.