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<p>The proteasome is an essential protein complex that, when dysregulated, can result in various diseases in
eukaryotic cells. As such, understanding the enzymatic activity of the proteasome and what can alter it is crucial
to elucidating its roles in these diseases. This can be done effectively by using activity-based fluorescent
substrate probes, of which there are many commercially available that target the individual protease-like subunits
in the 20S CP of the proteasome. Unfortunately, these probes have not displayed appropriate characteristics for
their use in live cell-based assays. In the work presented here, we have developed a set of probes which have
shown improved fluorescence properties and selectivity towards the proteasome compared to other cellular
proteases. By including unnatural amino acids, we have found probes which can be utilized in various
applications, including monitoring the effects of small molecule stimulators of the proteasome in live cells and
comparing the relative proteasome activity across different cancer cell types. In future studies, we expect the
fluorescent probes presented here will serve as tools to support the discovery and characterization of small
molecule modulators of proteasome activity.
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