Getting selective with cyclic peptides. Hitting the right target

A peptide library is a little like a regular book library. The peptide library has a number of amino acids or books all lined up in a specifically ordered system. We know and understand each book, and we can then make changes and easily see what effect those changes have. These libraries are useful for designing drugs and understanding how peptides interact and bind.  

 A cyclic peptide is a ring structure, which is formed from any two ends of the peptide joining together. These are very stable structures and bioactive molecules that have already been approved in therapeutics such as antibiotics, antifungals, anticancer, and immunosuppressants. There are many cyclic peptides derived from nature, but the chance of finding the optimal ligand to bind onto a new target is low but can be accelerated through the use of a peptide library and a technology called mRNA display pioneered by our Partner Investigator Hiroaki Suga at the University of Tokyo.  Like a book library that contains different books with a large amount of information, our peptide libraries comprise nearly a trillion different cyclic peptides with varying ring sizes and compositions. Some members of this large cyclic peptide library are just the right size and shape to bind to a given protein target and we can identify the sequences that bind using a molecular (DNA) barcode system.  

 Using these cyclic peptides to understand and improve binding to proteins of interest has been a key aim for CIPPS researchers Chief Investigator Professor Richard Payne, Partner Investigator Professor Hiroaki Suga, Associate Investigators Professor Joel Mackay and Dr Toby Passioura and centre researchers Dr Charlotte Franck and Dr Alex Norman.  

Bromodomain and extra-terminal (BET) family of proteins control the expression of distinct sets of genes that are important for cell proliferation, cell-cycle progression and apoptosis. They have been identified as promising therapeutic targets for diseases that range from cancer to inflammatory disorders, heart disease and diabetes. Because BET proteins play roles in many cellular processes, inhibitors or drugs would need to be specific and controlled. However, these BET proteins are like quadruplets all wearing the same outfit; it is very difficult to tell them apart and there are currently no molecules available that specifically bind to one bromodomain and not to the other family members. 

 Our team has discovered and characterised new cyclic peptides that bind specifically and with high affinity to one of the quadruplets. This research demonstrates the power of cyclic peptides to discriminate between very similar proteins with high potency and hint that differences in conformational dynamics might modulate the affinity of these domains for particular ligands. This fundamental work sets the scene for optimising selective cyclic peptide molecules for future applications in anticancer drug development. 

 Reference: https://www.sciencedirect.com/science/article/abs/pii/S0969212623001636  

DOI: 10.1016/j.str.2023.05.009 

Paper: Discovery and characterization of cyclic peptides selective for the C-terminal bromodomains of BET family proteins 

Centre members involved: Richard Payne, Charlotte Franck, Hiroaki Suga, Joel Mackay