5 research outputs found
Tunable Heparan Sulfate Mimetics for Modulating Chemokine Activity
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
Tailored Glycopolymers as Anticoagulant Heparin Mimetics
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
Tunable Heparan Sulfate Mimetics for Modulating Chemokine Activity
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