51³Ô¹ÏÍø

Our latest publication is out now in RSC Chemical Biology

This publication describes the work we have done on characterising the full protein target set of protein-protein interaction inhibitors known as alpha-helix mimetics. This work was primarily carried out by Amrita Date during her PhD in the group and Archie Wall during his EPSRC funded postdoc position. Hannah Kiely-Collins made some of the earliest compounds during her MSci project which was supervised by former PhD student Theo Flack. The project was carried out in collaboration with Ed Tate at 51³Ô¹ÏÍø and Andy Wilson at the University of Birmingham. We are excited to have this work featured in the journal .

The dysregulation of protein-protein interactions (PPIs) in disease states is well established, yet they are challenging to target, owing to the large surface area and featureless nature of protein binding interfaces. For targeting helix-mediated interactions, α-helix mimetics present a promising strategy. These are versatile small molecule scaffolds, capable of mimicking the hotspot residues on an α-helix. A wide range of such scaffolds have been reported, yet their target protein selectivity in the context of a whole proteome requires further exploration. Here, we report the affinity-based protein profiling of three structurally distinct classes of α-helix mimetics, N-substituted oligobenzamides, pyrrolopyrimidines, and oxopiperazines. This represents the first direct cross-comparison of different helix mimetic scaffolds, revealing significant differences in proteome-wide selectivity.