Targeting protein-protein interactions (PPIs) is a promising approach in the development of drugs for many indications. 14-3-3 proteins are a family of phosphoprotein-binding molecules with critical functions in dozens of cell signaling networks. 14-3-3s are abundant in the central nervous system, and the small molecule fusicoccin-A (FC-A), a tool compound that can be used to manipulate 14-3-3 PPIs, enhances neurite outgrowth in cultured neurons. New semisynthetic FC-A derivatives with improved binding affinity for 14-3-3 complexes have recently been developed. Here, we use a series of screens that identify these compounds as potent inducers of neurite outgrowth through a polypharmacological mechanism. Using proteomics and X-ray crystallography, we discover that these compounds extensively regulate the 14-3-3 interactome by stabilizing specific PPIs, while disrupting others. These results provide new insights into the development of drugs to target 14-3-3 PPIs, a potential therapeutic strategy for CNS diseases.

在许多适应症的药物开发中，靶向蛋白质-蛋白质相互作用（PPI）是一种有前途的方法。14-3-3蛋白是磷酸蛋白结合分子家族，在许多细胞信号网络中具有关键功能。14-3-3在中枢神经系统中含量很高，小分子融合霉素A（FC-A）是一种可用于操纵14-3-3 PPI的工具化合物，可促进神经元在神经元中的生长。最近已开发出对14-3-3复合物具有改善的结合亲和力的新型半合成FC-A衍生物。在这里，我们使用一系列的筛选方法，通过多药理学机制将这些化合物确定为神经突生长的有效诱导剂。使用蛋白质组学和X射线晶体学，我们发现这些化合物通过稳定特定的PPI而不破坏其他PPI来广泛调控14-3-3相互作用组。这些结果为靶向14-3-3 PPI的药物开发提供了新的见识，这是中枢神经系统疾病的潜在治疗策略。