Spatiotemporal control of protease activity by photoactivatable inhibitors

Proteases are involved in the regulation of many biological
processeses in the body. Dysregulation of protease activity plays a
role in many diseases, including cancer, Alzheimer’s disease and
hypertension. Therefore, proteases are considered as interesting
drug targets. It is clear that we need both fundamental understanding
of protease function and efforts to develop protease targeting drugs.
Some protease targeting drugs have already entered the clinics.
Unfortunately, others have failed in clinical trials; one major reason
for this comprises side-effects resulting from inhibition elsewhere in
the body.
In this research project, we will synthesize molecules that allow
local inhibition of proteases after a certain trigger. Specifically, we will
design and synthesize protease inhibitors that become active after
irradiation with light. In order to do this in an efficient and safe way,
we will develop novel protecting groups that disintegrate upon
irradiation with UV or visible light. We will illustrate the power of this
approach by the synthesis of photoactivatable inhibitors for
caspases, matrix metallo proteases and aspartyl proteases and by
application to cancer cell lines as well as more fundamental
questions in developmental processes. Overall, this project will
provide a novel strategy to examine proteases in space and time,
and to overcome possible side effects of protease inhibition in
treatment of disease.