Designing molecular spanners to throw in the protein networks

Proteins govern most aspects of cellular life and, through specific interfaces, are typically involved in intricate protein-protein interaction (PPI) networks and signaling pathways. Subtle up- or downregulation of key protein functions and PPIs results in disease; still, the preferred option to contrast a protein's role in disease and healthy conditions alike remains its outright shutdown through orthosteric ligands that block its active site. Here, we explore subtler alternatives to modulate proteins and PPIs. Driven by a view of proteins as dynamic entities, we discuss ways to identify allosteric binding sites which, when targeted by tailored ligands, can induce significant changes in a protein's active site, and lead to agonistic or antagonistic effects. We also review the selective regulation of specific PPIs-either direct or allosteric-and show that effects can be stabilizing as well as destabilizing, depending on how a protein's conformational equilibrium is shifted.