Tunable Heparan Sulfate Mimetics for Modulating Chemokine Activity

Abstract

Heparan sulfate (HS) glycosaminoglycans participate in critical biological processes by modulating the activity of a diverse set of protein binding partners. Such proteins include all known members of the chemokine superfamily, which are thought to guide the migration of immune cells through their interactions with HS. Here, we describe an expedient, divergent synthesis to prepare defined HS glycomimetics that recapitulate the overall structure and activity of HS glycosaminoglycans. Our approach uses a core disaccharide precursor to produce a variety of differentially sulfated glycopolymers. We demonstrate that a specific trisulfated mimetic antagonizes the chemotactic activity of the proinflammatory chemokine RANTES with potency similar to that of heparin, without inhibiting serine proteases in the blood coagulation cascade. Our work provides a general strategy for modulating chemokine activity and dissecting the pleiotropic functions of HS/heparin through the presentation of defined sulfation motifs within polymeric scaffolds.

Interactions of the Chemokine CCL5/RANTES with Medium-Sized Chondroitin Sulfate Ligands

“…Recent work by Hsieh and co-workers demonstrated the potential of GAG mimetics in preventing CCL5-mediated inflammation. (Sheng et al, 2013) Results in this study can potentially improve specificity and potency of such a strategy.…”

“…Disruption of such interactions has been shown to effectively attenuate the migration of leukocytes in vivo (Appay et al, 1999; Hoogewerf et al, 1997; Proudfoot et al, 2003), suggesting that inhibiting CCL5-GAG interactions might prove to be a viable anti-inflammatory strategy. (Sheng et al, 2013). However, rational design of modulators of such interactions must be built on a clear understanding of the biophysical interactions among components in these protein-carbohydrate complexes, yet obtaining detailed information on the structure and dynamics of protein-GAG complexes is challenging.…”

“…Earlier study by Hoogewerf et al showed GAGs easily triggered CCL5 oligomerization both in vitro and on cell surfaces (Hoogewerf et al, 1997). Moreover, understanding the interactions of larger GAGs with chemokines will also aid in the development of potential anti-inflammatory agents, including GAG mimetics (Sheng et al, 2013). …”

Heparin-Mimicking Polymers: Synthesis and Biological Applications

“…111 (d) Heparin mimicking polymers by ROMP to contain pendant disaccharides with three sulfates fabricated by Hsieh-Wilson and co-workers. 118 (e) 3,4,6-Sulfoglucosamines copolymerized by free radical polymerization by Miura and co-workers. 121 …”

Prospects for the therapeutic application of sulfated polysaccharides of brown algae in diseases of the cardiovascular system: review

“…Accordingly, GAG mimetics can interact with other macromolecules and can modulate the effects of signal molecules in cells. (Volpi 2006;Sheng et al 2013). Thus, the structural similarity of fucoidan and heparan sulfate predetermines therapeutic potential of fucoidan as agent with diverse functions.…”