Department of Pathology, University of Michigan, Ann Arbor, USA.
Expert Rev Mol Med. 2012 Jul 26;14:e16. doi: 10.1017/erm.2012.10.
Protein-protein interactions (PPIs) control the assembly of multi-protein complexes and, thus, these contacts have enormous potential as drug targets. However, the field has produced a mix of both exciting success stories and frustrating challenges. Here, we review known examples and explore how the physical features of a PPI, such as its affinity, hotspots, off-rates, buried surface area and topology, might influence the chances of success in finding inhibitors. This analysis suggests that concise, tight binding PPIs are most amenable to inhibition. However, it is also clear that emerging technical methods are expanding the repertoire of 'druggable' protein contacts and increasing the odds against difficult targets. In particular, natural product-like compound libraries, high throughput screens specifically designed for PPIs and approaches that favour discovery of allosteric inhibitors appear to be attractive routes. The first group of PPI inhibitors has entered clinical trials, further motivating the need to understand the challenges and opportunities in pursuing these types of targets.
蛋白质-蛋白质相互作用 (PPIs) 控制着多蛋白复合物的组装，因此这些接触点具有作为药物靶点的巨大潜力。然而，该领域既有令人兴奋的成功案例，也有令人沮丧的挑战。在这里，我们回顾了已知的例子，并探讨了 PPI 的物理特征，如亲和力、热点、解吸率、埋藏表面积和拓扑结构，如何影响寻找抑制剂的成功机会。该分析表明，简洁、紧密结合的 PPI 最适合抑制。然而，很明显，新兴的技术方法正在扩大“可成药”蛋白接触的范围，并增加了针对困难靶点的难度。特别是，类似天然产物的化合物库、专门针对 PPI 的高通量筛选以及有利于发现别构抑制剂的方法似乎是有吸引力的途径。第一批 PPI 抑制剂已进入临床试验，这进一步激发了人们对理解这些类型靶点的挑战和机遇的需求。
