Heparan Sulfate Glycomimetics via Iterative Assembly of “Clickable” Disaccharides

Abstract

Heparan sulfate (HS) glycosaminoglycans are widely expressed on the mammalian cell surfaces and extracellular matrices and play important roles in variety of cell functions. Studies on the structure-activity relationships of HS have long been hampered by the challenges in obtaining chemically defined HS structures with unique sulfation patterns. Here, we report a new approach to HS glycomimetics based on iterative assembly of clickable disaccharide building blocks that mimic the disaccharide repeating units of native HS. Variably sulfated clickable disaccharides were facilely assembled into a library of mass spec-sequencible HS-mimetic oligomers with defined sulfation patterns by solution-phase and solid-phase iterative syntheses. Microarray and surface plasmon resonance (SPR) binding assays corroborated with the molecular dynamic (MD) simulation and confirmed that these HS-mimetic oligomers bind protein fibroblast growth factor 2 (FGF-2) in a sulfation-dependent manner consistent with that of the native HS. This work established a general approach to HS glycomimetics that can potentially serve as alternatives to native HS in both fundamental research and disease models.

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

“…It should be pointed out that in parallel to our work, Niu and coworkers recently submitted the synthesis of head to tail HS mimetics through the alkyne azide [3+2] cycloaddition reaction. [40] Sulfated monosaccharide serine conjugate has been utilized to form glyco-amino acid oligomers to mimic HS with only homo-oligomers prepared without varying sulfation patterns within the molecule. [41] These reports combined with our work suggest linear HS mimetics strategies provide an exciting approach to expedite the synthesis of HS-like compounds and faciliate the understanding of the fascinating biological functions of HS.…”

“…In addition to our study, other "head-to-tail" HS mimetics have also been reported (Section S2). [42,43] Thus, reducing the complexity of synthesis through the "head-to-tail" linear mimetics formation represents a new direction to expedite the preparation of HS mimics and facilitate the understanding of their exciting biological functions. 33, 33 a-z) on FGF-2 interaction with heparin through a competition SPR assay.…”