Chemistry Weekly Seminar - Dr. Chris Phenix, University of Saskatchewan
Chris Phenix, Assistant Professor in the Department of Chemistry, University of Saskatchewan, will present a seminar at 1:30 pm in ARTS 146.
Title
Design, Synthesis and Biological Validation of Chemical Tools for Studying Biological Processes in Plants, Animals and Humans
Abstract
Research in the Phenix lab is focused on developing new chemical tools to study biological processes in plants, animals and humans. Although we have a significant number of collaborative projects within the areas of chemical biology, drug discovery, probe development, medicine and crop sciences, most of our effort is dedicated towards discovering new agents for molecular imaging proteins using nuclide- and fluorescence-based techniques.
All mammalian cells have thousands of tiny, acidic and membrane-bound organelles called lysosomes. Critical for maintaining cell health, lysosomes are home to ~60 different hydrolytic enzymes that degrade a variety of biomolecules. Dynamic changes in lysosomal function has been recently observed in a variety of diseases including cancer, atherosclerosis, arthritis and neurodegenerative diseases; all of which has led to tremendous scientific interest in lysosomal biochemistry. However, lysosomal function is complex and dynamic, and our scientific understanding has been hampered due to a lack of chemical tools designed to uncover the activity of lysosomal enzymes and/or lysosome function over the course of disease progression. To address this gap, my lab has developed novel probes for assessing lysosomal function, inactivators of lysosomal enzymes and molecular imaging agents designed to uncover the activity of important lysosomal enzymes in live cells and animals, tissues and human samples.
In this seminar, I will talk about our efforts to develop probes for Cathepsin B, a lysosomal cysteine protease that is a biomarker and drug target for aggressive cancers. We have developed a new class of fluorescent and radioactive reporter molecules designed to accumulate nearby the activity of Cathepsin B. Residualizing reporter groups could enable a substrate-based approach for molecular imaging protease activity by exploiting the catalytic power of the target enzyme operating in the tumour environment. One novel reporter molecule, which has NIR fluorescent emission and accumulates in lysosomes in a pH dependent manner, may be a powerful new lysotracker dye enabling critical experiments for understanding lysosomal biology.
In another project, we have developed mechanism-based inactivators, fluorescent probes and PET radiotracer candidates for β-glucocerebrosidase (GCase). GCase is a lysosomal glycosidase that hydrolyzes glycosphingolipids and its activity rapidly drops in aggressive Parkinson disease. Consequently, GCase is widely considered an exciting drug target leading to tremendous investment towards the design of GCase-boosting therapies for treating Parkinson’s. Our new chemical tools, which represent some of the most potent and GCase-selective probes and inhibitors, are attracting significant interest by the pharmaceutical industry. Profiling and imaging GCase activity, in response to GCase-boosting therapies, is of tremendous interest to the Parkinson’s community. One of our best inhibitors represents the first compound capable of inactivating GCase in the brains of live mice at low microgram doses. Not only is this compound an important lead towards GCase-selective probes and radiotracers, but we have shown it can be used to selectively inactivate GCase in live cell and animals thus enabling biochemical studies designed to unravel the consequences of reduced enzyme activity on lysosomal function. Time permitting, short summaries of other collaborative projects will also be presented.
Date: Friday, September 16, 2022
Time: 1:30 pm
Place: ARTS 146