Robin J. LEATHERBARROWProf., Chemistry, Imperial College London

Pharmaceutical routes toward therapeutic intervention typically involve situations where an enzyme or a receptor is the protein target for drug discovery. Generally, small molecule inhibitors are used to compete with the binding of substrates or ligands; these are then developed into therapeutics with specific pharmacokinetic properties. The undoubted success of the pharmaceutical industry is testimony to the effectiveness of this approach. However, there are a decreasing number of suitable target proteins and new approaches are needed in order to unlock alternative targets, with the most obviously underexploited class of target is where interactions occur between two or more large proteins.

Despite being underrepresented within the therapeutic portfolio, it is the case that the majority of biologically and medicinally relevant molecular interactions involve interactions between pairs of proteins. However, the prevailing pharmaceutical industry view remains that protein interfaces are inherently "undruggable," or at best are extremely unpromising candidates for therapeutic intervention. This is because there are considerable difficulties in targeting such systems: the interactions are typically over a large area and involve ill-defined pockets; some protein-protein interactions are extremely tight and/or have off rates that are prohibitively high. The result is that while their potential is widely acknowledged, most drug discovery efforts avoid protein-protein complexes. This presents both an opportunity and a challenge: development of new technologies or methodologies to compensate for the currently available inadequate paradigms would have the potential to open up new untapped areas of healthcare.

This talk will review the current status of protein-protein interaction inhibitors and describe some successes we have had developing constrained peptides to mimic interacting protein surfaces, and also how microfluidics can be used to good effect to screen for inhibitors in these systems.