Glycosaminoglycan Mimetic Precision Glycomacromolecules with Sequence-Defined Sulfation and Rigidity Patterns

Sulfated glycosaminoglycans (sGAGs) such as heparan sulfate (HS) are structurally diverse linear polysaccharides that are involved in many biological processes and have gained interest as antiviral compounds. Their recognition is driven by a complex orchestra of structural parameters that are still under intense investigation. One distinct characteristic is the incorporation of sulfation patterns including highly sulfated and non -sulfated sequences that provide variations in flexibility and conformation, which in turn impact the biological function of sGAGs. However, these distinct features have not yet been fully realized in the synthetic preparation of sGAG mimetics. Here, we present the synthesis of three groups of sulfated glycomacromolecules as sGAG mimetics: (i) globally sulfated glycooligomers, (ii) glycooligomers with sequence-defined sulfation patterns, and (iii) a globally sulfated glycooligomer-oligo-L-proline hybrid structure. The complete synthesis, including chemical sulfation, was conducted on solid support, enabled by the introduction of a commercially available photocleavable linker allowing for the preservation of sensitive sulfates during cleavage of the products. Structures were obtained in good purity and with high degrees of sulfation demonstrating the wide applicability of this methodology to prepare tailor-made sulfated glycomacromolecules and similar sGAG mimetics. Structures were tested for their anticoagulant properties showing activity similar to their natural HS counterpart and significantly lower than HP.

Automated summary

Sulfated glycosaminoglycans (sGAGs) are important in various biological processes and have potential as antiviral compounds. The structure and sulfation patterns of sGAGs play a key role in their biological function. However, synthesizing sGAG mimetics is still challenging. In this study, three groups of sulfated glycomacromolecules were successfully synthesized, demonstrating the wide applicability of this method. The synthesized structures had high purity and sulfation degree, and showed anticoagulant properties similar to natural HS.