Abstract:

Glycans regulate many biological processes, but weak and transient carbohydrate-protein interactions are difficult to detect in native settings, and disease-associated glycosylation changes are often hard to exploit. In this seminar, I will present two complementary chemical strategies that convert glycan recognition into actionable readouts for discovery and targeting. First, I will introduce carbohydrate-directed labeling probes (CDLPs), a modular class of ligand-directed covalent probes in which a carbohydrate ligand and a bioorthogonal handle flank a tuned electrophile. Carbohydrate binding positions the electrophile near nucleophilic residues on carbohydrate-binding proteins (CBPs), trapping fleeting interactions as stable covalent adducts for detection and profiling. CDLPs function in purified systems, live cells, and native proteomes, enabling detection of millimolar-affinity interactions in a ligand- and competition-dependent manner. A 6′-sialyllactose CDLP selectively labels CD22 on B cells, and quantitative chemoproteomics with sialyllactose- and lactose-CDLPs maps complementary, ligand-specific networks while uncovering proteins without prior carbohydrate annotations. Second, I will describe lectin drug conjugates (LDCs) that leverage cancer-associated increases in high mannose N-glycans to deliver toxins selectively to cancer cells. Moreover, cells with low high mannose levels can be sensitized by co-treatment with a type I mannosidase inhibitor. Together, these approaches demonstrate how chemical tools can both illuminate glycan-binding biology and translate aberrant glycosylation into therapeutic opportunity.

Speaker Bio: