Stapled by design: Peptide-based therapeutic leads targeting rheumatoid arthritis

University of Edinburgh

Active award

Student: Marie Bluntzer

Year Award Started: 2017

The interactions between proteins in a cell control many biological processes and so present attractive targets for therapeutic intervention. However, in contrast to the normal “lock and key” analogy for the development of small molecule drugs targeting enzyme activity, the surfaces involved in protein-protein interactions (PPIs) tend to be much larger and have less well-defined binding pockets. Thus PPIs present more challenging targets for therapeutic intervention, and they have largely been ignored.
One emerging approach to targeting PPIs is to examine the structural information available for the protein complex, and to look for a short helical section within one of the proteins at the interface. Generating this excised portion of the structure in the laboratory leads to a molecule which is able to displace its parent protein from the protein complex, thus disrupting the normal biological function. A small number of drugs are currently under development based on this strategy. Sadly, short sections of the protein backbone (called peptides) do not tend to adopt the same structure as they have in the parent protein – so a technique termed “stapling” has been developed to constrain the structure of the peptide sequence, ideally to give the desired helix. As well as enhancing the binding capability of the therapeutic peptide, this approach has recently been shown to have the added benefits of improving its stability under biological conditions (important for potential drug candidates) and improving cell penetration (widening the scope of the approach).
As yet, stapled peptides cannot be designed using computational techniques. In this project we will develop new tools for the prediction of the structure of stapled peptide sequences (Michel) and apply them to the rational design of stapled peptides (Hulme) which interact with two key proteins which are important in the inflammatory signalling pathways in rheumatoid arthritis (UCB).


Research area: Infections, inflammation or immunology


Dr Alison Hulme
School of Chemistry
Dr Julien Michel
School of Chemistry

UCB Biopharma SPRL