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

肽是药物发现的重要分子，但固有的性质，如生物利用度差和快速处置阻碍了它们的临床应用。然而，这些缺点已经使用诸如环化和氮杂肽的方法克服。结合后两种方法，我们设想了一种有效的环氮杂肽的制备方法 （氮杂环肽），其表现出用于药物开发的显著属性。巨噬细胞是一类重要的白色血细胞，其识别受损和外来物质（例如，细胞碎片、微生物和癌细胞），它们在称为吞噬作用的过程中吞噬和消化这些细胞，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，在疾病状态期间，例如黄斑变性，显著的巨噬细胞功能可以通过产生活性氧和放大炎症而加重发炎组织，从而引起进一步的组织损伤。可以调节巨噬细胞活性的分子是相关的靶点，因为它们具有增强细胞碎片清除而不产生活性氧物质和累积的炎症因子的潜力。靶向CD36清道夫受体，这是常见的巨噬细胞的表面上和整体参与氧化脂质和脂蛋白碎片的吸收，我们已经构思了环状氮杂肽，可以调节炎症反应，有利于清除，而不产生活性氧。拟议研究的核心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，这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.