Protease as therapeutic targets and diagnostic markers
Skaggs School of Pharmacy and Pharmaceutical Sciences
Our research is focused on the detection and characterization of proteolytic enzymes associated with disease. Many of the proteases that we study are found in infectious organisms, cancerous tissues, immune cells or human biofluids. Following in depth characterization of the target proteases, we develop potent and selective inhibitors to inactivate these enzymes or fluorogenic substrates to monitor catalytic activity.
We use a platform technology called Multiplex Substrate Profiling by Mass Spectrometry (MSP-MS) to uncover the global proteolytic activity in complex biological samples and have successfully applied it to blood, pancreatic cyst fluid, gastric juice of cancer cells and microbiobes. Our workflow also includes proteomic and peptidomics analysis to identify the proteases and endogenous substrates in the biological sample. Knowledge of which proteases are functionally active in diseased tissue and not active in healthy tissue allow us to 1) develop inhibitors to inactivate the target enzyme, 2) generate protease-activated imaging agents to locate the disease or 3) develop protease- activated drugs to aid in the delivery of toxic compounds to the site of disease. Our group is highly collaborative and we routinely generate substrate specificity profiles of endo proteases, aminopeptidases or carboxypeptidases that have been isolated from diverse life forms such as bacteria, fungi, viruses, plants, protozoa, mammals ticks, crustaceans and nematodes.
B.S. (2000) and Ph.D (2005) in Biochemistry, National University of Ireland, Galway; Postdoctoral Fellow (2005-2011) University of California, San Francisco; Associate Specialist (2011-2015) University of California, San Francisco.
Awards and Honors:
North America representative to International Proteolysis Society (2017 to 2021); Bioanalysis Young Investigator Award (2013), UCSF Center for Bio-Entrepreneurship Team Award (2009); UC Education Abroad Program Scholar (2002); Irish Research Council for Science, Engineering & Technology Post-Graduate Fellowship (2002); Enterprise Ireland Post-Graduate Fellowship (2001); Alpha Technologies Undergraduate Award (2000).
Director of Center for Protease Inhibitor Design; President of the International Proteolysis Society (2019-2021); Chair of Gordon Research Seminar in “Proteolytic Enzymes & Their Inhibitors”; National Center of Leadership in Academic Medicine Fellowship (2017)
- Principles of Pharmaceutical Sciences and Drug Development (SPPS 263A)
- Pharmaceutical Chemistry (SPPS 223)
- Developed a mass spectrometry based substrate profiling assay
- Identified tissue degrading from bat fungus
- Developed potent anti-parasitic compounds that target the parasite proteasome
- Developed a protease activity assay that provides differential diagnosis of pancreatic cysts
- Lapek JD Jr et al (2019) “Quantitative Multiplex Substrate Profiling of Peptidases by Mass Spectrometry”, Mol Cell Proteomics. May;18(5):968-981.
- Bibo-Verdugo B, et al (2019) “The Proteasome as a Drug Target in the Metazoan Pathogen, Schistosoma mansoni” ACS Infect Dis. Oct 11;5(10):1802-1812
- O’Donoghue et al (2019) “20S Proteasome as a Drug Target in Trichomonas vaginalis” Antimicrob Agents Chemother Oct 22;63(11):e00448-19
- Adem S et al (2020) “Giant magnetoresistive biosensors for real-time quantitative detection of protease activity” Sci Rep. May 14;10(1):7941. doi: 10.1038/s41598-020-62910-2.
Selected Publications (view more)
- Experience in protease assay development,
- Successful collaboration history with biotechnology and pharmaceutical companies
- Protease substrate profiling of complex biological samples
- Protease/peptidase inhibitor development
- Mass Spectrometry, Proteomics