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。大多数分泌和许多跨膜蛋白很难与小分子药物靶向，因为它们缺乏典型的药物结合位点。解决这一问题的一种方法是通过阻止分泌和膜蛋白向细胞表面的运输来间接抑制它们。在这项拨款申请中，我们描述了辅酶转运蛋白，一种以底物特异性方式抑制蛋白质分泌的环磷脂多肽。我们发现辅酶蛋白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)，这一过程需要新生多肽的N-末端的信号序列。CoTransin通过一种未知的机制干扰Sec61易位通道对少数信号序列的开放能力。这个项目的主要目标是设计和合成新的化学工具，使我们能够剖析辅酶转运蛋白生物学活性的分子基础。共转运蛋白

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