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Tunable Heparan Sulfate Glycomimetics for Modulating Chemokine Activity

Citation

Sheng, Gloria J. (2014) Tunable Heparan Sulfate Glycomimetics for Modulating Chemokine Activity. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/JQ2Z-EN67. https://resolver.caltech.edu/CaltechTHESIS:05272014-224131184

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 distinct subsets of immune cells through their interactions with HS proteoglycans on endothelial cell surfaces. Animal-derived heparin polysaccharides have been shown to reduce inflammation levels through the inhibition of HS-chemokine interactions; however, the clinical usage of heparin as an anti-inflammatory drug is hampered by its anticoagulant activity and potential risk for side effects, such as heparin-induced thrombocytopenia (HIT).

Here, we describe an expedient, divergent synthesis to prepare defined glycomimetics of HS that recapitulate the macromolecular structure and biological activity of natural HS glycosaminoglycans. Our synthetic approach uses a core disaccharide precursor to generate a library of four differentially sulfated polymers. We show that a trisulfated glycopolymer antagonizes the chemotactic activities of pro-inflammatory chemokine RANTES with similar potency as heparin polysaccharide, without potentiating the anticoagulant activities of antithrombin III. The same glycopolymer also inhibited the homeostatic chemokine SDF-1 with significantly more efficacy than heparin. Our work offers a general strategy for modulating chemokines and dissecting the pleiotropic functions of HS/heparin through the presentation of defined sulfation motifs within multivalent polymeric scaffolds.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:glycosaminoglycans, heparin, heparan sulfate, chemokines, RANTES, SDF
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Hsieh-Wilson, Linda C.
Thesis Committee:
  • Dougherty, Dennis A. (chair)
  • Arnold, Frances Hamilton
  • Mazmanian, Sarkis K.
  • Hsieh-Wilson, Linda C.
Defense Date:30 July 2013
Record Number:CaltechTHESIS:05272014-224131184
Persistent URL:https://resolver.caltech.edu/CaltechTHESIS:05272014-224131184
DOI:10.7907/JQ2Z-EN67
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8403
Collection:CaltechTHESIS
Deposited By: Gloria Sheng
Deposited On:29 May 2014 22:00
Last Modified:04 Oct 2019 00:05

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