Heparan sulfate synthesis

We have introduced strategies for the parallel combinatorial synthesis of heparan sulfate oligosaccharides to provide unprecedented numbers of distinct compounds. To demonstrates the utility of the modular approach, the library of heparan sulfate oligosaccharides was used to probe structural features of heparan sulfate for inhibiting the protease, BACE-1. The cleavage of amyloid precursor protein by the protease BACE-1 is a key step in generating amyloid plaques, which is a typical indication of Alzheimer disease. The observed complex variation in activity with structural changes support the view that important functional information is embedded in HS sequences. Furthermore, the most active derivative provided an attractive lead compound for the preparation of more potent compounds that may find use as therapeutic agents for Alzheimer’s and other diseases. The large collection of HS oligosaccharides has been used to develop a micro-array for ligand identification for HS-binding proteins. To confirm that specific HS oligosaccharides can induce cellular activation, we have developed a cell surface labeling strategy in which CMP-Neu5Ac is modified by a synthetic HS oligosaccharide that is then transferred to N-glycan of living cell deficient in HS-biosynthesis using a recombinant sialyl transferase. The resulting cells have been used in binding and cellular activation studies to validate array screenings. 

Lu W, Zong C, Chopra P, Pepi L, Xu Y, Amster IJ, Liu J, Boons GJ (2018) Controlled chemoenzymatic synthesis of heparan sulfate oligosaccharides. Angew Chem Int Ed 57(19):5340-5344. 

Capicciotti CJ, Zong C, Sheikh MO, Sun T, Wells L, Boons GJ (2017) Cell-surface glyco-engineering by exogenous enzymatic transfer using a bifunctional CMP-Neu5Ac derivative. J Am Chem Soc 139(38):13342-13348. 

Zong C, Venot A, Li X, Lu W, Xiao W, Wilkes JL, Salanga CL, Handel TM, Wang L, Wolfert MA, Boons GJ (2017) Heparan sulfate microarray reveals that heparan sulfate-protein binding exhibits different ligand requirements. J Am Chem Soc 139(28):9534-9543. 

Zong C, Huang R, Condac E, Chiu Y, Xiao W, Li X, Lu W, Ishahara M, Wang S, Ramiah A, Stickney M, Azadi P, Amster IJ, Moremen KW, Wang L, Sharp JS, Boons GJ (2016) Integrated approach to identify heparan sulfate ligand requirements of Robo1. J Am Chem Soc 138(39):13059−13067.