Pharmaceutical Sciences Seminar: “Uncovering the substrate specificity of proteases for use in development of inhibitors, diagnostics and therapeutics”

ISEB 1010, 419 Physical Sciences Quad, Irvine, CA, United States

Anthony O’Donoghue
Associate Professor
UC San Diego – Skaggs School of Pharmacy and Pharmaceutical Sciences
Abstract:
Proteases are ubiquitous in all life forms and it is important to be able to develop biochemical tools that can distinguish between closely related proteases. We have developed an assay known as multiplex substrate profiling by mass spectrometry (MSP-MS) that uses a mixture of highly diverse synthetic peptides as a protease substrate library. Cleavage by a protease of any one of the 2,964 peptide bonds in this library can be detected by tandem mass spectrometry. We have used this method to uncover the substrate specificity profile of several hundred proteases and used this information to develop potent and selective inhibitors. In addition, we have generated proteolytic signatures of complex biological samples such as plasma, urine, saliva and cyst fluid that facilitated the discovery of proteases that are active only in diseased tissues. We use this information to develop activity-based diagnostics and protease-activated therapeutics. This research seminar, will provide an overview of the MSP-MS assay and the downstream applications.