Heparan sulfate-mimicking glycopolymers bind SARS-CoV-2 spike protein in a 
length- and sulfation pattern-dependent manner

Abdulsalam, Hawau; Li, Jiayi; Loka, Ravi S.; Sletten, Eric T.; Nguyen, Hien M.

doi:10.1021/acsmedchemlett.3c00319

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Heparan sulfate-mimicking glycopolymers bind SARS-CoV-2 spike protein in a length- and sulfation pattern-dependent manner

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Sletten, Eric T.
Peter H. Seeberger - Automated Systems, Biomolekulare Systeme, Max Planck Institute of Colloids and Interfaces, Max Planck Society;

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Citation

Abdulsalam, H., Li, J., Loka, R. S., Sletten, E. T., & Nguyen, H. M. (2023). Heparan sulfate-mimicking glycopolymers bind SARS-CoV-2 spike protein in a length- and sulfation pattern-dependent manner. ACS Medicinal Chemistry Letters, 14(14), 1411-1418. doi:10.1021/acsmedchemlett.3c00319.

Cite as: https://hdl.handle.net/21.11116/0000-000D-C3D6-5

Abstract

Heparan sulfate-mimicking glycopolymers, composed of glucosamine (GlcN)–glucuronic acid (GlcA) repeating units, bind to the receptor-binding subunit (S1) and spike glycoprotein (S) domains of the SARS-CoV-2 spike protein in a length- and sulfation pattern-dependent fashion. A glycopolymer composed of 12 repeating GlcNS6S-GlcA units exhibits a much higher affinity to the S1 protein (IC₅₀ = 13 ± 1.1 nM) compared with the receptor-binding domain (RBD). This glycopolymer does not interfere in angiotensin-converting enzyme 2 binding of the RBD. Although this compound binds strongly to the S1/membrane-fusion subunit (S2) junction (K_D = 29.7 ± 4.18 nM), it does not shield the S1/S2 site from cleavage by furin─a behavior contrary to natural heparin. This glycopolymer lacks iduronic acid, which accounts for 70% of heparin. Further, this compound, unlike natural heparin, is well defined in both sulfation pattern and length, which results in fewer off-target interactions with heparin-binding proteins. The results highlight the potential of using polymeric heparan sulfate (HS) mimetics for the therapeutic agent development.