Adam Linstedt ‘82, Ph.D.
Carnegie Mellon University

“Biosensors and Cell-based Screening to Identify Drugs Targeting Golgi-based O-glycosylation"

Tuesday, Nov 7, 2017
3:50 pm Pre-seminar tea
4:10 pm Seminar begins
Biology 19

Student Lunch: Students interested in joining Dr. Linstedt for lunch should RSVP by emailing me ASAP since spaces are limited. Then plan to meet in B19 after the talk (about 1pm). Commons dining room vouchers will be distributed at that time.

Abstract: Site-specific O-glycosylation taking place in the Golgi complex is a modification of proteins that controls their activities in crucial ways. Major diseases including chronic kidney disease and cancer involve misregulation of this process. Other diseases, viral outbreaks being an example, depend on this process to carryout their destruction. A family of closely related isozymes initiates site-specific O-glycosylation with individual isozymes acting on distinct sets of proteins. This avails a therapeutic opportunity in the sense that a single disease-relevant isozyme may be targeted leaving the others to carryout their myriad functions critical to normal health. But, crucially, there are no known drugs targeting these isozymes. To enable high-throughput screening for drug-like inhibitors, we are developing cell-based fluorescent sensors of O-glycosylation mediated by the ppGalNAc-T isozymes. Initial screening identified an inhibitor of ppGalNAc-T3 that opposed upregulation of the isozyme in driving metastatic-like behavior of cancer cells and it blocked ppGalNAc-T3-mediated glycan-masking of FGF23 thereby reducing secretion of intact FGF23, a possible treatment of chronic kidney disease. These findings commence a pharmacological approach for the ppGalNAc-transferase family and suggest that targeting specific GalNAc-transferases will yield new therapeutics.