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.

Heparin and its low molecular weight derivatives are clinical therapeutics used to treat and prevent blood clots, but are prone to side effects and contamination. Here we describe the design and expedient synthesis of heparin-based glycopolymers that are potent and potentially safer mimetics of heparin. The mimetics exhibited strong activity against proteases in the coagulation cascade and prolonged blood clot times in human plasma with efficacies similar to those of clinical anticoagulants.

[structure: see text] The richly oxygenated C(1)-C(30) polyol segment of amphidinol 3 has been synthesized in protected form. Incorporated in this long chain are 10 of the 25 stereogenic centers housed in the target. The asymmetric pathway that has been developed is based on the efficient union of three independently prepared subunits.

Not to clot: Heparin and its low‐molecular‐weight derivatives are clinical therapeutics used to treat and prevent blood clots. The synthesis of heparin‐based glycopolymers that are potent and potentially safer mimetics of heparin is described. The mimetics exhibited activity against proteases (FXa and FIIa) in the coagulation cascade and prolonged blood clot times in human plasma with efficacies similar to those of clinical anticoagulants. ATIII=antithrombin III.

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