Download Insight into cellular waste management

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.”