Peptidomimetics Unlock New Potential in Drug Discovery

Collaborating with the Universities of Bristol and Leeds, researchers at the University of Birmingham have effectively demonstrated a method for modifying peptides to transform them into potentially useful tools for drug discovery and disease diagnosis.

Traditional targets for drug discovery include kinases and proteases. Because these proteins have clearly defined "binding sites" for their substrates - the molecules that the enzymes interact with - they make appealing targets. Nowadays, it is not too difficult to create molecules that resemble the substrate and either inhibit or alter the target's function.

On the other hand, most biological processes, including those of enzymes, are regulated by interactions between proteins, or so-called protein-protein interactions (PPIs). Blocking PPIs may make a much wider range of drug targets possible because PPIs are far more common than traditional drug discovery targets.

PPIs have historically been regarded as too challenging to employ as therapeutic targets, though, due to the larger size of their binding sites and the reduced number of grooves or pockets to which small molecules can attach. Finding new drugs to target these crucial targets starts with understanding how PPIs arise and how to control them. 

The group concentrated on a PPI involving β-strand formation at the interface in the recently published study, which was published in Chemical Science. One particular kind of secondary structure that helps proteins form three dimensions is called a β-strand. The scientists were able to demonstrate that a small peptide sequence from the region of the protein where the β-strand forms binds to the target more quickly and firmly by altering its backbone. 

Our modification uses relatively simple chemistry and has taught us about how peptides bind to their targets in a β-strand conformation and how to control binding. This in turn opens up the path to drug discovery for β-strand mediated PPIs targets.”

Andy Wilson, Study Lead Researcher and Professor, School of Chemistry, University of Birmingham

The group has demonstrated how this could be accomplished for a particular class of PPI, the SIM/SUMO interaction, which is essential for protein stability, stress response, and cell cycle regulation. The next stage will be to show that the strategy can be applied to a variety of PPIs.

Source:
Journal reference:

Cawood, E. E., et al. (2024) Understanding β-strand mediated protein-protein interactions: tuning binding behavior of intrinsically disordered sequences by backbone modification. The Royal Society of Chemistry. doi.org/10.1039/d4sc02240h

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