Department of Chemistry, Imperial College London, London SW72AZ, United Kingdom.
Bioorg Med Chem. 2012 Jan 15;20(2):614-21. doi: 10.1016/j.bmc.2011.06.042. Epub 2011 Jun 21.
Clostridium difficile, a leading cause of hospital-acquired bacterial infection, is coated in a dense surface layer (S-layer) that is thought to provide both physicochemical protection and a scaffold for host-pathogen interactions. The key structural components of the S-layer are two proteins derived from a polypeptide precursor, SlpA, via proteolytic cleavage by the protease Cwp84. Here, we report the design, synthesis and in vivo characterization of a panel of protease inhibitors and activity-based probes (ABPs) designed to target S-layer processing in live C. difficile cells. Inhibitors based on substrate-mimetic peptides bearing a C-terminal Michael acceptor warhead were found to be promising candidates for further development.
艰难梭菌是医院获得性细菌性感染的主要原因，其表面覆盖有一层致密的表层（S 层），该层被认为既能提供物理化学保护，又能为宿主-病原体相互作用提供支架。S 层的主要结构成分是两种由多肽前体 SlpA 通过蛋白酶 Cwp84 的蛋白水解切割产生的蛋白质。在这里，我们报告了一组蛋白酶抑制剂和活性探针（ABPs）的设计、合成和体内特性，这些抑制剂和探针旨在针对活的艰难梭菌细胞中的 S 层加工。基于带有 C 末端迈克尔受体弹头的模拟底物肽的抑制剂被发现是进一步开发的有希望的候选物。
