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Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Med. Chem. Lett. 2023, 14, 10, 1411-1418
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Heparan Sulfate-Mimicking Glycopolymers Bind SARS-CoV-2 Spike Protein in a Length- and Sulfation Pattern-Dependent Manner

  • Hawau Abdulsalam
    Hawau Abdulsalam
    Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States
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  • , 
  • Jiayi Li
    Jiayi Li
    Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States
    More by Jiayi Li
  • , 
  • Ravi S. Loka
    Ravi S. Loka
    Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States
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  • , 
  • Eric T. Sletten
    Eric T. Sletten
    Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Muehlenberg 1, 14476 Potsdam, Germany
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    Orcidhttps://orcid.org/0000-0003-2177-2969
  • , and 
  • Hien M. Nguyen*
    Hien M. Nguyen
    Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States
    *Email: [email protected]
    More by Hien M. Nguyen
    Orcidhttps://orcid.org/0000-0002-7626-8439
Cite this: ACS Med. Chem. Lett. 2023, 14, 10, 1411–1418
Publication Date (Web):September 29, 2023
https://doi.org/10.1021/acsmedchemlett.3c00319
Copyright © 2023 American Chemical Society
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    Abstract

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    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 (KD = 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.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.3c00319.

    • General synthetic procedure of the key intermediates and glycopolymers; 1H and 13C NMR spectra for glycopolymers; and biological assay procedures (PDF)

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