Protease are regulated at the level of their activity in both normal and disease conditions. Thus it is difficult to monitor the dynamic nature of this regulation in the context of a live cell or whole organism using standard genomic or proteomic methods. Our laboratory has developed a series of small molecule activity based probes that specifically bind the active form of protease targets through an enzyme catalyzed chemical reaction. These reagents freely penetrate cells and can be used to enrich complex proteomic samples for monitoring of global patterns of protease activity as well as to directly image protease activity in live cells and whole animals. They can also be used to monitor the efficacy and selectivity of small molecule protease inhibitor drugs. We are currently applying these probes to study the role of specific proteases in the process of angiogenesis and metastasis in mouse models of cancer as well as during the process of inflammation in mouse models of atherosclerosis and asthma. In addition, we have developed probes that bind caspases associated with the process of apoptosis. These reagents allow the direct non-invasive imaging of apoptosis in vivo. We are currently developing these tools to further study the cell biology of tumor response to chemotherapy. Advances in development and applications of activity based probes will be presented.

Small molecule probes of protease function: Applications to molecular imaging and drug discovery

243rd National Meeting (2012)

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