End-functionalized glycopolymers as mimetics of chondroitin sulfate proteoglycans

Abstract

Glycosaminoglycans are sulfated polysaccharides that play important roles in fundamental biological processes, such as cell division, viral invasion, cancer and neuroregeneration. The multivalent presentation of multiple glycosaminoglycan chains on proteoglycan scaffolds may profoundly influence their interactions with proteins and subsequent biological activity. However, the importance of this multivalent architecture remains largely unexplored, and few synthetic mimics exist for probing and manipulating glycosaminoglycan activity. Here, we describe a new class of end-functionalized ring-opening metathesis polymerization (ROMP) polymers that mimic the native-like, multivalent architecture found on chondroitin sulfate (CS) proteoglycans. We demonstrate that these glycopolymers can be readily integrated with microarray and surface plasmon resonance technology platforms, where they retain the ability to interact selectively with proteins. ROMP-based glycopolymers are part of a growing arsenal of chemical tools for probing the functions of glycosaminoglycans and for studying their interactions with proteins.

Studies of Highly-Ordered Heterodiantennary Mannose/Glucose-Functionalized Polymers and Concanavalin A Protein Interactions Using Isothermal Titration Calorimetry

“…37 We chose this exo -norbornene 4 because it has been reported that 4 undergoes ring-opening metathesis polymerization (ROMP) much faster than its endo -counterpart, 38 and allows for multivalent display of the ligands at defined, chemically controlled intervals to promote multivalent binding. 39 Furthermore, this polymerizable scaffold 4 increases the structural rigidity of the neoglycopolymers and allows efficient access to the corresponding copolymers between α-mannose and β-glucose units. 39 Accordingly, the Mitsunobu coupling of 4 with alcohol linker 5 40 provided 6 in 98% yield (Scheme 1).…”

“…39 Furthermore, this polymerizable scaffold 4 increases the structural rigidity of the neoglycopolymers and allows efficient access to the corresponding copolymers between α-mannose and β-glucose units. 39 Accordingly, the Mitsunobu coupling of 4 with alcohol linker 5 40 provided 6 in 98% yield (Scheme 1). Removal of the tert -butyl silyl (TBS) ether group afforded 82% yield of primary alcohol 7 , which served as a glycosyl acceptor in the glycosylation with trichloroacetimidate donor 8 mediated by 20 mol% of trimethylsilyl triflate (TMSOTf).…”

Multi-dimensional glycan microarrays with glyco-macroligands

“…[11,13,33] Fig. 4 Glycopolymer-based glycoarray: a duel end functionalized mucin like glycopolymer with alkyne on one end and Texas Red dye on the other end [24], b mucin like glycopolymer presentation that mimics native mucin [40], c biotin end functionalized glycopolymer immobilized glass slide [26], d glycopolymer formation at different illumination times [41], e O-cyanate end functionalized glycopolymer immobilized on amine functionalized glass slide [27], f O-cyanate chain-end functionalized glycopolymer pre-complexed and immobilized with boronic acid ligands of different sizes [28]. Modified from Ref.…”

“…Hsieh-Wilson et al synthesized a biotin end functionalized glycopolymer that mimic chondroitin sulfate proteoglycans via ring-opening metathesis polymerization technique [26], which were employed for microarray and SPR applications. Both sulfated CS-E and non-sulfated CS-C glycopolymers were immobilized onto streptavidin coated glass slides by high-precision contact-printing robot, which delivers nanoliter volumes of glycopolymer onto glass slides.…”

“…In the past decades, various glycopolymeric molecules have been investigated for studying carbohydrate-protein interactions and biomedical research and applications, such as for multivalent inhibitors and antagonists development. For example, different multivalent carbohydrate molecules like glycodendrimers [16][17][18][19][20][21][22], glycopolymers [23][24][25][26][27][28], glycoliposomes [29][30][31][32], neoglycoproteins [11,13,33], and glyconanoparticles [34] as glyco-macroligands were developed to attain more specific and strong carbohydrate-protein interactions. It is acknowledged that not only the multivalency of the carbohydrates affect the binding specificity but also the orientation of the carbohydrates on the solid surface affects the interactions significantly, i.e.…”