Protease Substrate Profiling and Inhibitor Design
Skaggs School of Pharmacy and Pharmaceutical Sciences
Dr. O’Donoghue’s laboratory interests lie in the detection and characterization of proteolytic enzymes that are involved in disease. In particular, we are interested in understanding the role of peptidases/proteases at host-pathogen and tumor-stroma interfaces. Our research utilizes a mass spectrometry based platform technology to uncover the global proteolytic activity in complex biological samples such as the secretions of cancer cells and infectious organisms. Our workflow also includes in-depth proteomic analysis to identify the enzymes. Knowledge of which peptidases are functionally active in diseased tissue and not active in healthy tissue allow us to 1) develop peptidase inhibitors to shut down the function, 2) generate peptidase-activated imaging agents to locate the disease or 3) develop peptidase-activated drugs to aid in the delivery of toxic compounds to the site of disease. Using this technology, we have uncovered novel proteolytic activities in gastric juice, pancreatic cyst fluid, synovial fluid, serum and neutrophil extracts. In addition our group is highly collaborative and we routinely generate substrate specificity profiles of endo- and exo-peptidases that have been isolated from diverse organisms that includes ticks, crustaceans and parasitic worms.
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:
Treasurer and 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).
Chair of 2016 Gordon Research Seminar in “Proteolytic Enzymes & Their Inhibitors”
- Developed a mass spectrometry based peptidase substrate profiling assay
- Identified tissue degrading peptidase from bat fungus
- Developed potent anti-malarial compounds that target the Plasmodium proteasome
- Developed a protease activity assay that provides differential diagnosis of pancreatic cysts
- O’Donoghue, et al (2012) “Global identification of peptidase specificity by multiplex substrate profiling” Nature Methods, 9(11): 1095–100
- O’Donoghue et al. (2015) “Destructin-1 is a collagen-degrading endopeptidase secreted by Pseudogymnoascus destructans, the causative agent of white-nose syndrome” Proc Natl Acad Sci USA. 112:7478-83
- Li H, O’Donoghue AJ, et al. (2016) “Structure- and function-based design of Plasmodium-selective proteasome inhibitors” Nature, 11;530(7589):233-6
- Ivry SL, et al (2017). Global Protease Activity Profiling Provides Differential Diagnosis of Pancreatic Cysts. Clin Cancer Res. 2017 Aug 15; 23(16):4865-4874. PMID: 28424202
- Winter MB, et al (2017) Immunoproteasome functions explained by divergence in cleavage specificity and regulation Elife. 28;6.
- 18 years’ experience in protease assay development,
- Successful collaboration history with biotechnology and pharmaceutical companies
- Protease substrate profiling of complex biological samples
- Peptidase inhibitor development
- Mass Spectrometry, Proteomics