2015 Chemical Biology Program Retreat

Friday, September 11, 2015
9:00am - 4:30pm
Multipurpose Room, Student Community Center
Keynote Speaker: Charles Craik
(click here to download PDF program)

Global Analysis and Visualization of Proteolysis in Disease

Proteases represent the largest class of post-translational modifying enzymes in the human proteome. An estimated 2% of human genes encode 687 proteases or protease-like homologs. With every protein having a cradle to grave relationship with proteolysis, uncovering the substrate specificity of these proteases is central to understanding their physiological role in homeostasis and disease. We have developed methods to functionally “profile” a given protease and identify sequences of its preferred substrate. These sequences provide a pharmacophore of the active site of the enzyme and can also be used to identify inhibitors as well as potential natural substrates. We recently extended our technology to globally detect the activity and reveal the substrate specificity of any endo or exo protease in a complex biological sample. We have applied this methodology to simultaneously detect all protease activity in indications of infectious disease and cancer. The resulting proteolytic signatures are proving beneficial for monitoring disease progression and for defining the biological role of the proteases involved. Our understanding of the molecular recognition properties of proteases and the tools that we developed to study them in complex biological samples led us to develop methods that can visualize their enzymatic activity in vivo. Conformationally selective, recombinant antibody-based probes that are highly selective for a given enzyme permit non-invasive imaging of the protease as a biomarker for early detection and prognosis of cancer and for validating the protease as a potential therapeutic target. The approach that we are developing for identifying these probes is proving to be a general method for identification of antibody based probes for extracellular enzymes and receptors. Our studies are providing a better understanding of both the chemical make-up and the biological importance of these critical proteins.