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Synthesis of 3-O-sulfonated heparan sulfate octasaccharides that inhibit the herpes simplex virus type 1 host–cell interaction

Nature Chemistry volume 3, pages 557–563 (2011)Cite this article

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Abstract

Cell surface carbohydrates play significant roles in a number of biologically important processes. Heparan sulfate, for instance, is a ubiquitously distributed polysulfated polysaccharide that is involved, among other things, in the initial step of herpes simplex virus type 1 (HSV-1) infection. The virus interacts with cell-surface heparan sulfate to facilitate host-cell attachment and entry. 3-O-Sulfonated heparan sulfate has been found to function as an HSV-1 entry receptor. Achieving a complete understanding of these interactions requires the chemical synthesis of such oligosaccharides, but this remains challenging. Here, we present a convenient approach for the synthesis of two irregular 3-O-sulfonated heparan sulfate octasaccharides, making use of a key disaccharide intermediate to acquire different building blocks for the oligosaccharide chain assembly. Despite substantial structural differences, the prepared 3-O-sulfonated sugars blocked viral infection in a dosage-dependent manner with remarkable similarity to one another.

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Figure 1: Specific 3-O-sulfonated octasaccharides 1 and 2 and retro-synthetic design of the corresponding α-methylated glycosides 3 and 4.
Figure 2: Preparation of disaccharide building blocks 6, 7, 8, 14 and 15.
Figure 3: Preparation of heptasaccharide acceptor 33.
Figure 4: Synthesis of target octasaccharide 4.
Figure 5: Synthesis of target octasaccharide 3.
Figure 6: Inhibition of HSV-1 infection of Vero cells by compounds 3 and 4.

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Acknowledgements

This work was supported by the National Science Council (NSC 97-2113-M-001-033-MY3, NSC 98-2119-M-001-008-MY2) and Academia Sinica. The authors thank P.G. Spear for providing HSV-1 (KOS) tk12.

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  1. Yu-Peng Hu and Shu-Yi Lin: These authors contributed equally to this work

Authors and Affiliations

  1. Genomics Research Center, Academia Sinica, 128, Section 2, Academia Road, Taipei, 115, Taiwan

    Yu-Peng Hu, Shu-Yi Lin, Medel Manuel L. Zulueta, Jing-Yuan Liu & Shang-Cheng Hung

  2. Department of Chemistry, National Tsing Hua University, 101, Section 2, Kuang-Fu Road, Hsinchu, 300, Taiwan

    Yu-Peng Hu & Shu-Yi Lin

  3. Institute of Molecular Biology, Academia Sinica, 128, Section 2, Academia Road, Taipei, 115, Taiwan

    Cheng-Yen Huang & Wen Chang

  4. Department of Applied Chemistry, National Chiao Tung University, 1001, Ta-Hsueh Road, Hsinchu, 300, Taiwan

    Shang-Cheng Hung

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Contributions

S-C.H. conceived the idea of HS synthesis, supervised students to carry out the experiments, drew and summarized the figures, and finalized the preparation of the manuscript. Y-P.H. and S-Y.L. synthesized the irregular HS octasaccharides 3 and 4, respectively. C-Y.H. carried out the inhibition experiments of HSV-1 with Vero cells. M.M.L.Z. participated in the discussion and wrote the manuscript. J-Y.L. initiated the work on the preparation of the oligosaccharide skeleton. W.C. supervised C-Y.H. on the inhibition study of HSV-1 infection.

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Correspondence to Shang-Cheng Hung.

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Hu, YP., Lin, SY., Huang, CY. et al. Synthesis of 3-O-sulfonated heparan sulfate octasaccharides that inhibit the herpes simplex virus type 1 host–cell interaction. Nature Chem 3, 557–563 (2011). https://doi.org/10.1038/nchem.1073

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