2019 Research Grant Award
£84,505.37 for years 1-3 only of a 42 month PhD starting October 2020 at the School of Pharmacy, UEA.
Grant Applicants:
Dr Andrew Beekman
One of the hallmarks of cancer is its ability to evade the immune system. Cancer cells can over-produce proteins which turn off the immune system and under-produce proteins which turn it on. Two of the proteins which control this are Programmed Death-1 (PD-1) and Programmed Death Ligand-1 (PD-L1). Controlling how these two proteins interact has led to treatments for many cancers, called immune checkpoint therapy, and the award of the Nobel Prize in 2018.
One way of controlling this interaction is using antibodies but these tend to be expensive and can have dangerous side effects. If small, drug-like molecules could be found which control this interaction then this treatment could become more widely available at a much lower cost. However, finding small molecules which control massive proteins is very challenging with current techniques.
The aim of this project is to use a new technique, developed in our lab, to make small molecules which can control this interaction. Peptides (small protein-like molecules) which control the interaction of PD-1/PD-L1 will be used to design small, drug-like molecules. Peptides are smaller than antibodies but are still broken down by enzymes in the cell and often are unable to reach the target tumour. Small molecules are able to overcome these problems by penetrating into tumours and cancer cells.
This study will take a peptide which controls PD-1/PD-L1 and separate it into two “semi” peptides. Small drug-like fragments can be attached to the semi peptides to create peptide-small molecule hybrids. If these hybrids are able to bind to the protein then we can assume the small fragment in some way mimics a section of the peptide. This process can be done with both semi peptides, identifying many small molecule fragments which mimic a section of the peptide. The small fragments can then be joined together to create a small molecule which possesses fragments known to mimic a section of the parent peptide, creating a small molecule which controls PD-1/PD-L1.
This study will make new small molecules which target a protein interaction, PD-1/PD-L1. This research will lead to the development of small molecules which could replace expensive antibodies, making immune checkpoint therapy more widely available. Proving that this method works on important protein interactions will encourage other researchers to use this technology on a variety of problems.
This research will be carried out by a Ph.D. student, resulting in the training of a student to become an independent researcher with the skills and knowledge to pursue a career in cancer research.
