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

Abstract

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.

Well-Defined Heparin Mimetics Can Inhibit Binding of the Trimeric Spike of SARS-CoV-2 in a Length-Dependent Manner

“…Synthetic oligosaccharides have been attached to polymers in a pendant manner to mimic the properties of heparin. 45,46 Well-defined heparin and HS mimetics in which HS oligosaccharides are linked in a head-to-tail manner 23,47 are expected to mimic more closely the structure of natural counterparts. It provided well-defined compounds including a compound composed of as many as 27 monosaccharides.…”

“…The methodology makes it possible to examine in a systemic manner the optimal length for binding. Very recently, another approach was reported for head-to-tail coupling of HS-like saccharide building blocks 47 by amide coupling of disaccharides that have amino-and carboxylic acid-containing linkers at the anomeric center and C-4 of the nonreducing end, respectively. The goal was to mimic compounds that resemble relatively short HS fragments, and it was found that a pseudohexasaccharide mimetic can bind to FGF2 with a similar affinity as a natural hexasaccharide.…”