Protein-protein interactions (PPIs) occur in complex networks. These networks are highly dependent on cellular context and can be extensively altered in disease states such as cancer and viral infection. In recent years, there has been significant progress in developing inhibitors that target individual PPIs either orthosterically (at the interface) or allosterically. These molecules can now be used as tools to dissect PPI networks. Here, we review recent examples that highlight the use of small molecules and engineered proteins to probe PPIs within the complex networks that regulate protein homeostasis. Researchers have discovered multiple mechanisms to modulate PPIs involved in host/viral interactions, deubiquitinases, the ATPase p97/VCP, and HSP70 chaperones. However, few studies have evaluated the effect of such modulators on the target's network or have compared the biological implications of different modulation strategies. Such studies will have an important impact on next generation therapeutics.

中文翻译：

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在蛋白质稳态中调节蛋白质-蛋白质相互作用网络。

蛋白质间相互作用（PPI）发生在复杂的网络中。这些网络高度依赖于细胞环境，并且可以在疾病状态（例如癌症和病毒感染）中发生广泛变化。近年来，在开发以正构（在界面）或变构为靶标单个PPI的抑制剂方面已取得重大进展。这些分子现在可以用作剖析PPI网络的工具。在这里，我们回顾了最近的例子，这些例子突出了小分子和工程蛋白在调节蛋白稳态的复杂网络中探测PPI的用途。研究人员发现了多种机制来调节参与宿主/病毒相互作用，去泛素酶，ATPase p97 / VCP和HSP70分子伴侣的PPI。但是，很少有研究评估此类调节剂对靶标的影响。的网络或已比较了不同调制策略的生物学含义。这样的研究将对下一代疗法产生重要影响。