Synthesis of Novel Bivalent Mimetic Ligands for Mannose-6-phosphate Receptors
Open Access
Author:
Marshall, Jared Scott
Area of Honors:
Chemistry
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
Dr. Gong Chen, Thesis Supervisor Przemyslaw Maslak, Thesis Honors Advisor Philip C. Bevilacqua, Faculty Reader
Keywords:
M6P GlcNAc-M6P hydrolase sorting mimetic ligands
Abstract:
Eukaryotic cells utilize mannose-6-phosphate (M6P)-containing N-linked glycans as signaling molecules for sorting hydrolases to various cellular destinations. Corresponding M6P receptors (MPRs) of these essential targeting signals have recently emerged as promising protein targets for targeted drug delivery for the treatment of lysosomal storage disease. Additionally, the discovery of these receptors has advanced the possibility of elucidating the complex interaction between M6P N-glycans and MPRs. Herein, the design and synthesis of novel bivalent mimetic ligands for MPRs, in particular cation-independent MPRs (CI-MPRs), is fully described. Following recent research, a GlcNAc-M6P motif has been implicated in the interaction between M6P N-glycans and MPRs and has consequently been incorporated for the first time in these mimetic ligands. M6P- and GlcNAc-M6P-containing building blocks, equipped with -NH2 and -CO2H handles, have been prepared and assembled with an ornithine linker through a series of amide coupling reactions. Efficient global deprotection protocols have also been developed.
