The Fehl Lab develops chemical tools (organic and biochemical) to target real-time biological processes in living systems. Our goal is to determine HOW cells use sugars, WHAT the functions of those sugars are, and WHEN these changes occur.
Answering these fundamental questions in biology will reveal new targets for therapy, especially in cancer, diabetes, obesity, and other diseases with metabolic components.
Our key target is the protein O-GlcNAc modification (serine/threonine O-linked N-acetylglucosamine), which modifies proteins as a glucose sensor. Thousands of proteins are known to be O-GlcNAcylated, including many transcription factors that regulate gene expression. In humans, only one enzyme adds O-GlcNAc (O-GlcNAc transferase, OGT) and only one enzyme removes O-GlcNAc (O-GlcNAc hydrolase, OGA). Thus, downstream pathways/mechanisms are needed to successfully separate therapeutically useful targets from healthy processes.
1. Chemical biology tools to identify protein O-GlcNAcylation in living cells. We develop tools that allow us to spy on sugar modifications on proteins in real-time and in defined areas of the cell (nucleus, cytoplasm, and other organelles).
“Spatiotemporal Proximity Labeling Tools to Track GlcNAc Sugar-Modified Functional Protein Hubs during Cellular Signaling.” Yimin Liu, Zachary M. Nelson, Ali Reda, and Charlie Fehl. ACS Chemical Biology (2022) in-press. DOI: https://doi.org/10.1021/acschembio.2c00282
“Synthesis and mammalian cell compatibility of light-released glycan precursors for controlled metabolic engineering.” Courtney A. Kondor, Jaggaiah N. Gorantla, Garry D. Leonard, and Charlie Fehl. Bioorganic & Medicinal Chemical (2022) in-press. DOI: https://doi.org/10.1016/j.bmc.2022.116918
2. Disease biology studies to track O-GlcNAc mechanisms in pathology. A key example is determining how hyperglycemia in diabetes and obesity contributes to cancer risk.
“Hyperglycemic O-GlcNAc transferase activity drives cancer stem cell induction in triple-negative breast cancer.” Saheed Ayodeji, Emily A. Teslow, Lisa A. Polin, Greg Dyson, Aliccia Bollig-Fischer, and Charlie Fehl. bioRxiv (2022) https://doi.org/10.1101/2022.03.14.484003
3. Chemical strategies to impact O-GlcNAc protein writes, erasers, and readers using chemical synthesis, medicinal chemistry, and biological assay development.
“Tools, Tactics, and Objectives to Interrogate Cellular Roles of O-GlcNAc in Disease.” Charlie Fehl and John A. Hanover. Nature Chemical Biology (2022) 18: 8-17. DOI: https://doi.org/10.1038/s41589-021-00903-6
“Chemical Synthesis and Biological Applications of O-GlcNAcylated Peptides and Proteins.” Groenevelt, Jessica M.; Corey, Daniel J.; Fehl, Charlie. ChemBioChem (2021) 22: 1854-1870. DOI: 10.1002/cbic.202000843