Wednesday, April 23, 2025
4/23/2025
Chemoenzymatic Synthesis of Libraries of Sulfoglycopeptides - Abstract The Zhu lab uses synthetic chemistry to answer questions related to post-translational modifications (PTMs) of proteins, specifically, O-glycosylation and Tyrosine sulfation. Co-localization of Tyrosine sulfation and O- glycosylation on Serine/Threonine (CSOG) is an emerging global PTM pattern. CSOG exists in a variety of proteins, like G-protein coupled receptors, proteins of the hemostatic system, pathogen encoded proteins, and adhesion molecules. CSOG plays critical roles in modulating the binding/signaling networks through those proteins and their binding ligands/proteins. However, detailed information about how the cells or biological systems use fine-tuning CSOG structures to modulate corresponding binding/signaling pathways is lacking. One of the main gaps for studying the relationship is the lack of structure-defined molecules bearing CSOG. To fill up the gap, a generalized strategy is needed to synthesize those molecules so we can get access to the massive, diversified structures of CSOG. Then we can map out the relationship between the fine-tuning structures of CSOG and their corresponding binding/signaling pathways. We can also use these structure-defined molecules to develop reliable methods for characterizing CSOG from different proteins. Furthermore, we can combine synthetic chemistry and computational chemistry to develop robust computational chemistry methods for predicting meaningful bindings and designing probes/molecules to target certain specific bindings. Our lab currently focuses on applying site-selective sulfation in chemoenzymatic synthesis of glycopeptides to provide a generalized strategy for the access to the complex molecules with CSOG. Towards this goal, our lab developed a Ag2O promoted method for large-scale synthesis of the two critical intermediates, GalN3-α-Fmoc- Ser/Thr, for future synthesis of all the needed 16 glyco-amino acids. We have achieved the synthesis of core 2 containing glyco-amino acid in gram scale. For site-selective sulfation, we developed 2-Cl-trityl protecting group as a new way for doing site-selective sulfation. For enzymatic extension of O-glycans on sulfoglycopeptides, our initial attempt demonstrated that the enzyme worked on the sulfoglycopeptide even with protecting groups on the sulfate groups. We expect to generalize this strategy to synthesize libraries of sulfoglycopeptides in this proposal. This MIRA funding will support us to use our generalized synthetic strategy to initiate the following major projects: (1) Build compound libraries to map out the complex network between COSG patterns and corresponding binding/signaling pathways; (2) Use structure-defined molecules with CSOG to develop reliable methods to characterize CSOG structures from different proteins; (3) Use our binding data and computational methods to develop robust computational chemistry methods to predict meaningful binding and design probes/molecules to target specific bindings.
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