Protein–protein interactions as druggable targets: recent technological advances

• New techniques have been developed to tackle PPI as drug targets.
• Fragment-based approaches established successfully to find PPI modulators.
• Stapled peptides as pharmacological tools and new class of therapeutics.
• Not only competitive inhibitors: stabilisers, interfacial and allosteric binders.
• Antibody-aided small molecule discovery for PPI.

Classical target-based drug discovery, where large chemical libraries are screened using inhibitory assays for a single target, has struggled to find ligands that inhibit protein–protein interactions (PPI). Nevertheless, in the past decade there have been successes that have demonstrated that PPI can be useful drug targets, and the field is now evolving fast. This review focuses on the new approaches and concepts that are being developed to tackle these challenging targets: the use of fragment based methods to explore the chemical space, stapled peptides to regulate intracellular PPI, alternatives to competitive inhibition and the use of antibodies to enable small molecule discovery for these targets.