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，驱动炎症、肿瘤血管生成和转移等病理生理过程。由于缺乏典型的药物结合位点，大多数分泌蛋白和许多跨膜蛋白难以被小分子药物靶向。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。在这项拨款申请中，我们描述了共转蛋白，一种环沉积肽，以一种底物特异性的方式抑制蛋白质分泌。我们发现共转蛋白阻断了分泌蛋白生命中最早的一个步骤：共翻译易位到内质网（ER），这一过程需要在新生多肽的n端有一个信号序列。通过一种未知的机制，协转蛋白干扰Sec61易位通道响应少数信号序列打开的能力。该项目的主要目标是设计和合成新的化学工具，使我们能够解剖共转蛋白生物活性的分子基础。cotransin

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