Drug targets are like cliff faces; chemists need to find key hand and foot holds on a protein’s surface in order to design small molecule drugs that modulate their function, and thus impact the biological pathways associated with a disease. At first glance, however, most disease targets appear as sheer glass surfaces, with no obvious routes to attack them.
This is the picture that researchers all too often see when targets are viewed in isolation outside of a cell, especially in static crystal structures that only capture a single snap-shot of a protein’s structural conformation. However, inside a cell, where it is hard to routinely look, targets are dynamic entities, with druggable pockets coming and going all the time for discovery and potential exploitation.
PROTEINi® (Protein-interference) is a live-cell assay system that probes for these hidden, or cryptic, druggable sites accross the whole human genome and simultaneously reveals those with a useful therapeutic function by registering a specific cellular response (or ‘phenotype’).
At the heart of PROTEINi lies the use of protein-fragment libraries, harbouring billions of different 3-dimensional shapes, to enable saturation level functional probing of target protein conformations for new druggable space. One library in particular (called a 'Phylomer' library) from our key partner Phylogica Ltd, is comprised of coding sequence fragments from a diverse array of bacteria and has demonstrated remarkably high functional hit rates in mammalian phenotypic assays (see example review by PM Watt in Nature Biotech 24(2) 2006).
The SITESEEKER® platform uses these functionally validated protein fragments to then rapidly inform the design of small molecule drugs with the same shape, providing a continuous pipeline of highly validated first-in-class drug discovery programmes for out-licensing to Pharma.