The Fehl Lab develops chemical tools (organic and biochemical) to target ongoing biological processes in living systems. This “bioorthogonality” enables real-time insight into signaling pathways that actively alter gene expression profiles (epigenetic effects) in cells as their environment changes. We use these insights to develop pharmacological probes, which are tested in disease model systems for therapeutic effects.
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 to avoid disrupting cellular metabolism/physiology that rely on bioorthogonal activation for sensitive protein labeling.
2. Machine-learning strategies to identify distinct and separable disease targets. We use deep informatic approaches to implicate specific target pathways involved in context-dependent O-GlcNAc signaling.
3. Design and synthesis of glycopeptidomimics as inhibitors of O-GlcNAcylated protein binding partners for therapeutic action. Modification allow chemoproteomic profiling of specific interaction partners.