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 a 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.

Significance: Human DEAD-box polypeptide 3 (DDX3) is an ATPase/RNA helicase involved in the replication of many viral pathogens. We reported herein the first inhibitor, to our knowledge, of the helicase binding site of DDX3 endowed with a broad spectrum antiviral activity [HIV-1 WT, HIV drug-resistant strains, Hepatitis C virus (HCV), Dengue virus (DENV), and West Nile virus (WNV)]. The good toxicity profile suggests that the DDX3 activity, although essential for viruses, could be dispensable to the cells, validating DDX3 as a pharmaceutical target. Our results clearly showed that DDX3 inhibitors could be exploited to treat HIV/HCV coinfections, emerging infectious diseases (such as DENV and WNV), and HIV-1 patients carrying drug-resistant strains. Each of these three medical conditions currently represents a major challenge for clinical treatment.