Glucocorticoids (GCs) have been widely used for decades as a first-line treatment for inflammatory and autoimmune diseases. However, their use is often hampered by the onset of adverse effects or resistance. GCs mediate their effects via binding to glucocorticoid receptor (GR), a transcription factor belonging to the family of nuclear receptors. An important aspect of GR's actions, including its anti-inflammatory capacity, involves its interactions with various proteins, such as transcription factors, cofactors, and modifying enzymes, which codetermine receptor functionality. In this review, we provide a state-of-the-art overview of the protein-protein interactions (PPIs) of GR that positively or negatively affect its anti-inflammatory properties, along with mechanistic insights, if known. Emphasis is placed on the interactions that affect its anti-inflammatory effects in the presence of inflammatory and microbial diseases.

Protein–protein interactions (PPIs) underlie most biological processes. An increasing interest to investigate the unexplored potential of PPIs in drug discovery is driven by the need to find novel therapeutic targets for a whole range of diseases with a high unmet medical need. To date, PPI inhibition with small molecules is the mechanism that has most often been explored, resulting in significant progress towards drug development. However, also PPI stabilization is gradually gaining ground. In this review, we provide a focused overview of a number of PPIs that control critical regulatory pathways and constitute targets for the design of novel therapeutics. We discuss PPI-modulating small molecules that are already pursued in clinical trials. In addition, we review a number of PPIs that are still under preclinical investigation but for which preliminary data support their use as therapeutic targets.