Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein–protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as “undruggable” targets, the last two decades have seen an increasing number of successful examples of PPI modulators, resulting in growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This perspective focuses on the hub-protein 14-3-3, which has several hundred identified protein interaction partners, and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide mimetics, and natural products.

中文翻译：

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14-3-3蛋白质-蛋白质相互作用的调节剂

蛋白质之间的直接相互作用对于调节其在生物途径中的功能至关重要。靶向蛋白质-蛋白质相互作用（PPI）的复杂网络现已被广泛认为是治疗性干预疾病状态的一种有吸引力的方法。尽管这是一项具有挑战性的工作，并且PPI长期以来一直被视为“不可负担的”目标，但在过去的二十年中，PPI调制器的成功实例不断增多，因此对该领域的兴趣日益浓厚。PPI调制需要新颖的方法以及多个学科的共同努力才能成为富有成效的战略。该观点集中在具有数百种已确定的蛋白质相互作用伙伴的集线蛋白14-3-3上，因此涉及广泛的细胞过程和疾病。这里，