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Expedient Synthesis of a Library of Heparan Sulfate Like “Head to Tail” Linked Multimers for Structure and Activity Relationship Studies

Zhang, Jicheng and Liang, Li and Yang, Weizhun and Ramadan, Sherif and Baryal, Kedar and Huo, Chang-Xin and Bernard, Jamie J. and Liu, Jian and Hsieh-Wilson, Linda and Zhang, Fuming and Linhardt, Robert J. and Huang, Xuefei (2022) Expedient Synthesis of a Library of Heparan Sulfate Like “Head to Tail” Linked Multimers for Structure and Activity Relationship Studies. . (Unpublished)

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Heparan sulfate (HS) plays significant roles in various biological processes such as inflammation, cell proliferation, and bacterial and viral infection. The inherent complexity of naturally existing HS has severely hindered the thorough understanding of the relationship between their diverse structures and biological functions. While HS syntheses have advanced significantly in recent years, preparation of HS libraries remains a tremendous challenge due to the difficulties in achieving high yields in glycosylation and sulfation reactions especially with longer glycans and the need to prepare multiple compounds. A new strategy to synthesize a library of HS-like pseudo-hexasaccharides has been developed to expedite library preparation. HS disaccharides were linked in a “head-to-tail” fashion from the reducing end of a module to the non-reducing end of a neighboring module to mimic native HS. Three differentially sulfated HS disaccharides were designed and prepared from a common intermediate. Conjugation of these modules using amide chemistry bypassed the need for challenging glycosylation reactions to extend the HS backbone. Combinatorial syntheses of 27 HS-like pseudo-hexasaccharides were achieved using these three HS modules. This new class of compounds mimicked well the native HS with their binding to fibroblast growth factor 2 (FGF-2) exhibiting similar structure-activity relationship trends as HS hexasaccharides. The ease of synthesis and the ability to mimic natural HS suggest the new head-to-tail linked pseudo-hexasaccharides could be an exciting tool to facilitate the understanding of HS biology.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Yang, Weizhun0000-0001-5522-4026
Ramadan, Sherif0000-0002-8639-4105
Baryal, Kedar0000-0003-1840-7485
Bernard, Jamie J.0000-0002-3800-2576
Liu, Jian0000-0001-8552-1400
Hsieh-Wilson, Linda0000-0001-5661-1714
Linhardt, Robert J.0000-0003-2219-5833
Huang, Xuefei0000-0002-6468-5526
Additional Information:The content is available under CC BY NC ND 4.0 License. We are grateful for financial supports from the National Institute of General Medical Sciences, NIH (R01GM072667, U01GM116262, and R44GM134738 to XH, JL and LH), National Institute of Environmental Health Sciences (R01ES030695 to JJB), and Michigan State University for financial support of our work. We would like to thank Prof. Erika Lisabeth (Assay Development and Drug Discovery Core, MSU) for her expert help on SPR data processing. Author’s competing interest statement. JL is a founder and chief scientific officer for Glycan Therapeutics. He has equity of the company and serves as a paid consultant. The author(s) declare that they have sought and gained approval from the relevant ethics committee/IRB for this research and its publication.
Funding AgencyGrant Number
Michigan State UniversityUNSPECIFIED
Subject Keywords:heparan sulfate; library synthesis; mimetic design; structure and activity relationship
Record Number:CaltechAUTHORS:20220711-653217000
Persistent URL:
Official Citation:Zhang J, Liang L, Yang W, et al. Expedient Synthesis of a Library of Heparan Sulfate Like “Head to Tail” Linked Multimers for Structure and Activity Relationship Studies. ChemRxiv. 2022. doi:10.26434/chemrxiv-2022-m03tb-v2
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:115472
Deposited By: George Porter
Deposited On:12 Jul 2022 14:18
Last Modified:12 Jul 2022 14:18

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