摘要

神经肽Y在G蛋白偶联受体的结合模式的结构见解和药物开发的后果

肽激素在调节体内多种活动中起着重要作用。它们中的许多通过g蛋白偶联受体(GPCR)传递活性,这是目前最有希望的药物靶点之一。因此,阐明配体的结合方式是必要的。虽然一些小分子系统已经被很好地描述,配体结合大的和灵活的多肽仍然是更具挑战性的。除了配体结合和受体激活,间接机制已被证明对GPCRs靶向药物发挥作用。这包括脱敏、内化和相应的潜在药物使用,如肿瘤靶向。因此,除了配体的结合外,还必须处理和研究内化问题,包括逮捕素的招募。因此,配体结合、结构动力学和内部化必须加以研究,以解决G蛋白偶联受体的药物开发问题。神经肽Y/胰腺多肽家族包含36个氨基酸肽,在人体内与四种不同的所谓Y受体结合。通过x射线分析、核磁共振、分子建模和交联质谱联用,我们最近可以确定NPY与Y1-和Y2受体的不同结合模式。 We could further demonstrate that chemical modification of the ligand, including fluorescence labeling, lipidization, and PEGylation significantly modifies the trafficking of the ligand. By labeling of the receptor with a novel template-assisted ligation strategy, we can follow ligand/receptor complexes in living cells. Furthermore, we identified a different mode of arrestin binding and recruitment. Neuropeptide Y1 and Y2 receptors have been shown to play a relevant role in different tumors. In breast cancer we demonstrated that human Y1 receptors are addressable by peptide conjugates using 99mTc or 18F PET-tracers. We now designed Y1 receptor selective peptides linked to different toxophors. Furthermore, we characterized the mechanism of direct and peptide-mediated uptake of tubulysin-related toxins. In the field of tumor therapy, peptide-drug conjugates are already well accepted. However, the concept of receptor-mediated internalization and subsequent tissue specific intracellular application is not limited to the selective addressing of tumors. This may open up a new field of targeted therapy by mid-sized drugs.


作者(年代):

安妮特G Beck-Sickinger



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