Many diseases are characterised by protein-protein interactions (PPIs) that occur within our cells. PPIs are often difficult to treat, as the large surface area of interaction between the proteins is difficult to disrupt with conventional small molecule drugs. Peptides, on the other hand, can disrupt PPIs, making them a potential modality for modern therapeutics targeting PPI-related diseases. Unfortunately, many peptides are unable to cross the cell membrane due to their size and other chemical characteristics including polarity and can only reach extracellular targets. There are, however, a range of peptides that are known to cross the cell membrane freely, called cell penetrating peptides (CPPs) but these cannot disrupt PPIs.  

In the case of Cancer, there are several key PPIs that help cells multiply, including the p53:MDM2 and p53:MDMX interactions, both of which have been widely studied. As these interactions are vital for Cancer to spread and are specific to the disease cell type, they represent exciting targets for therapies. 

Recently, our CIs Sonia Henriques and David Craik, and former-PhD student Grégoire Philippe published a study on a series of ‘angler peptides’ to disrupt these key interactions in Cancer. Angler peptides consist of a peptide drug fused to a cell penetrating peptide (CPP). The CPP should guide the peptide cargo into cells, in the same way angler fish use their light to guide them through dark waters. This strategy has been used by researchers previously to deliver cargo into cells and has often resulted in peptides that can enter a cell, but in doing so disrupt the membrane and cause cell death. Henriques and the team wanted to design a series of peptide fusions that would enter the cell without harming the membrane and go on to disrupt the p53:MDM2 and p53:MDMX interactions.  

Henriques and her team selected peptide KD3, a known inhibitor of p53:MDM2 and p53:MDMX interactions, as the cargo for their angler peptides. The team synthesised a series of angler conjugates consisting of this KD3 cargo fused to a range of CPPs, using standard peptide synthesis with cutting-edge conjugation techniques. The team used state-of-the-art Centre capabilities including fluorescence labelling, live cell microscopy and lipid vesicle studies to determine whether their Angler peptides could successfully enter cells and reach the intended target. Excitingly, the team identified two angler peptides that could enter cells and reach the intended target without disrupting the membrane. 

This study was published in the prestigious American Chemical Society’s Chemical Biology journal and has received over 1,300 article views and 5 citations.

The project represents a key cross-institutional collaboration between QUT and UQ and is an important output from our Flagship 2 within our Decode and Develop themes. 

Reference: Phillipe, J-B., 2021, https://pubs.acs.org/doi/pdf/10.1021/acschembio.0c00988