Design of synthetic agents that disrupt protein-protein interactions

破坏蛋白-蛋白相互作用（PPI）的低分子量化合物作为临床药物和研究细胞内PPI网络的化学探针具有巨大的潜在应用。然而，由于许多蛋白质的大而平坦的界面，破坏ppi是非常困难的，这些蛋白质通常缺乏结构上确定的空腔，这些空腔可以使类药物分子以热力学有利的方式结合。在这项研究中，我们研究了设计PPI抑制剂的模块组装策略，其中通过与连接剂的共价连接、金属配位或靶蛋白表面的化学连接来设计和组装小模块化合物，以创建多价剂。例如，为活性位点和PPI界面设计的两个模块的共价连接导致了一种有效的二价剂，可以破坏蛋白质戊烯基转移酶和K-Ras蛋白之间的瞬时蛋白质-蛋白质相互作用。这些药物对K-Ras c端寡肽的法尼化和香叶基化均有明显的抑制作用。此外，通过引入胍基和肽模拟物进行结构修饰，提高了药物的细胞渗透性，从而在细胞中产生亚微摩尔的FTase抑制剂。

Low-molecular-weight compounds that disrupt protein-protein interactions (PPIs) have tremendous potential applications as clinical agents and as chemical probes forinvestigating intracellular PPI networks. However, disrupting PPIs is extremely difficult due to the large, flat interfaces of many proteins, which often lack structurally defined cavities to which drug-like molecules could bind in a thermodynamically favorable manner. In this study, we examined the module-assembly strategy for designing PPI inhibitors, in which small module compounds are designed and assembled either by covalent linking with a linker, metal coordination, or chemical ligation on the targeted protein surface, to create a multivalent agent. For example, covalent linking of two modules designed for an active site and a PPI interface led to a potent bivalent agent that disrupt transient protein-protein interactions between protein prenyltransferases and K-Ras protein. These agents demonstrated significant inhibition activity against both farnesylation and geranylgeranylation of K-Ras C-terminal oligopeptide. Furthermore, structural modification by introducing guanidyl groups and peptidomimetics improved the cell permeation of agents, resulting in submicromolar inhibitors for FTase in cells.