Researchers from the University of Birmingham, along with the Universities of Bristol and Leeds, have shown that a simple modification to peptides could open up a new class of targets for drug discovery.
Enzymes like proteases and kinases have been the traditional targets in drug discovery. However, the team has found a way to modify peptides to make them useful for disease diagnostics and drug discovery.
Proteins are appealing targets because they possess clearly defined ‘binding sites’ for their substrates, which are the molecules that the enzymes interact with. Developing molecules that imitate the substrate and can inhibit or alter the function of the target has become relatively simple.
In contrast, the interactions between proteins, known as protein-protein interactions (PPIs), control most biological functions, including those of enzymes. PPIs are much more abundant than traditional drug discovery targets, so blocking PPIs potentially opens up a wider range of drug targets.
PPIs have traditionally been considered too challenging to target.it, the researchers were able to disrupt the protein-protein interaction. This finding provides a potential avenue for developing drugs that target PPIs by disrupting the β-strand formation at the interface. The study demonstrates the potential for using small molecule compounds to control PPIs and paves the way for future drug discovery efforts targeting these challenging protein interactions. The team hopes that their work will contribute to the development of new therapies for a range of diseases, including cancer and neurodegenerative disorders. The researchers are continuing to investigate other PPIs and are optimistic about the potential for developing new drugs that target these interactions. The study’s findings represent a significant step forward in the field of drug discovery and open up new possibilities for targeting challenging protein-protein interactions.The team demonstrated that the modification allowed the peptide to bind more quickly and strongly to its target. According to lead researcher Professor Andy Wilson, the simple chemistry used in the modification has provided valuable insights into the binding of peptides to their targets in a β-strand conformation and how to regulate this binding. This discovery has the potential to advance drug discovery for β-strand mediated PPIs targets. The team focused on the SIM/SUMO interaction, which is crucial for protein stability, stress response, and the cell cycle. The next phase of their research will involve demonstrating how this modification can be applied to other types of PPIs.The method can be applied to various PPIs.
The study was conducted by the Wilson team at the University of Birmingham and supported by EPSRC Programme and BBSRC strategic Longer and Larger (sLoLa) awards.
