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Gerjan de Bruin Leiden Institute of Chemistry Insight into cellular waste management In drug innovation, chemical knowledge and experience are of great value, as the research of Gerjan de Bruin shows. He developed a suite of chemical tools to visualize and control the activity of the waste treatment plants of human cells, the proteasomes. These large protein complexes are therapeutic targets in the treatment of various cancers and autoimmune diseases. By Willy van Strien Gerjan de Bruin is fascinated by drug innovation. He got his master’s degree at Utrecht University and is currently conducting his PhD research in Leiden. Just like households, cells have to get rid of their garbage. They contain proteasomes that degrade proteins that are damaged or have become useless. When proteasomes are inhibited, proteins accumulate leading to cell death, especially in cancer cells. That is why they are a target for anti-cancer therapies. “To develop safe and effective drugs, one must be able to measure proteasome activity and monitor the effect of candidate drugs”, Gerjan de Bruin explains. He developed a suite of tools to do this. A proteasome is a cylindrical complex where waste proteins are led into. Inside, bonds between constituting amino acids are broken at active sites. These sites come in three types that break bonds with different characteristics. In addition to the active sites that all cells have in common, immune cells, such as white blood cells, have an extra set of sites that are slightly different variants of the common sites. Firstly, to visualize the activity of proteasomes, De Bruin constructed three probes. Each probe binds to one active site and carries a green, blue or red fluorescent colour. After labelling with these probes, proteasomes are denaturated and the active sites are separated by gel electrophoresis, giving either three (for non-immune cells) or six (for immune cells) bands on the gel. The intensity of the bands is proportional to the relative amount of the active sites. “This enables us to measure the activity of all six active sites simultaneously”, De Bruin states. Secondly, he designed proteasome inhibitors that only inhibit one of the active sites. Thirdly, he showed that tumour cells of patients with one of several white blood cell malignancies harbour proteasomes with a high amount of immune type active sites. These tumour cells could be killed by selective inhibition of the immune type active sites. “This opens the possibility to develop drugs that attack immune-cell derived tumours but are not destructive for non-immune cells. Such drugs will have less side effects than proteasome inhibitor drugs currently used.”