Substrate-Selective Inhibitors of Secretory and Membrane Protein Biogenesis

描述（由申请人提供）：分泌和跨膜蛋白介导细胞间通讯，驱动病理生理过程，如炎症、肿瘤血管生成和转移。大多数分泌蛋白和许多跨膜蛋白难以用小分子药物靶向，因为它们缺乏典型的药物结合位点。解决这个问题的一种方法是通过阻止分泌蛋白和膜蛋白转运到细胞表面来间接抑制它们。在本申请中，我们描述了cotransin，一种以底物特异性方式抑制蛋白质分泌的环缩酚肽。我们发现cotransin阻断了分泌蛋白生命中最早的步骤之一：共翻译易位到内质网（ER）中，这是一个需要新生多肽N端信号序列的过程。通过一种未知的机制，cotransin干扰Sec61易位通道响应少数信号序列而打开的能力。该项目的主要目标是设计和合成新的化学工具，使我们能够剖析cotransin生物活性的分子基础。共转蛋白

DESCRIPTION (provided by applicant): Secreted and transmembrane proteins mediate intercellular communication, driving pathophysiological processes such as inflammation, tumor angiogenesis, and metastasis. Most secreted and many transmembrane proteins are difficult to target with small-molecule drugs, as they lack typical drug binding sites. One approach to this problem is to inhibit secreted and membrane proteins indirectly, by preventing their transport to the cell surface. In this grant application, we describe cotransin, a cyclodepsipeptide that inhibits protein secretion in a substrate-specific manner. We discovered that cotransin blocks one of the earliest steps in the life of a secreted protein: cotranslational translocation into the endoplasmic reticulum (ER), a process that requires a signal sequence at the N-terminus of a nascent polypeptide. By an unknown mechanism, cotransin interferes with the ability of the Sec61 translocation channel to open in response to a minority of signal sequences. The major goal of this project is to design and synthesize new chemical tools that will allow us to dissect the molecular basis of cotransin's biological activity. cotransin